Re: Reprogramming of fatty acid metabolism in cancer 2019 nature

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이 논문을 제대로 읽어내지 못하면 

암세포 굶기기를 위해 탄수화물 거의 금지, 좋은 지방섭취를 권장하는데

지방산을 암세포가 에너지원으로 사용하잖아라고 인식할 듯...

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Reprogramming of fatty acid metabolism in cancer

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• Review Article
• Open access
• Published: 10 December 2019

Cancer Metabolism

Reprogramming of fatty acid metabolism in cancer

• Nikos Koundouros & 
• George Poulogiannis 

British Journal of Cancer volume 122, pages4–22 (2020)Cite this article

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Abstract

A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

암 세포의 공통된 특징 중 하나는 

ATP 및 세포 성장, 분열, 생존에 필요한 대분자의 생산을 유지하기 위해 

대사 경로를 재구성하는 능력입니다.

 특히, 

지방산 대사의 변화는 

암에서 중요한 역할을 한다는 점에서 다시 한 번 주목받고 있습니다. 

지방산은 

세포막의 구조적 구성 요소로서의 주요 역할 외에도 

중요한 2차 신호 전달체로 작용하며, 

에너지 생산의 연료원으로 활용될 수 있기 때문입니다. 

이 리뷰에서는 암 세포가 지방산 대사를 재편하는 메커니즘을 네 가지 주요 연구 분야에 초점을 맞춰 살펴보겠습니다. 

(1) 세포 내 지방산 풀의 신생합성과 외부 섭취의 역할. 

(2) 분자적 이질성과 암 유발 신호 전달 경로(예: PI3K–AKT–mTOR 신호 전달)가 지방산 대사를 조절하는 메커니즘. 

(3) 지방산이 종양 미세환경 재편을 통해 암 진행 및 전이에 필수적인 매개체로 작용하는 역할. 

(4) 암에서 지방산 대사를 표적으로 삼는 치료 전략 및 고려 사항. 

암 유발 신호전달과 조절되지 않은 지방산 대사 사이의 복잡한 상호작용에 초점을 맞춘 추가 연구는

 새로운 대사 취약점을 발견하고 

표적 치료의 효과를 향상시키는 데 

큰 잠재력을 가지고 있습니다.

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Background

Fatty acids (FAs) are the main building blocks of several lipid species, including phospholipids, sphingolipids and triglycerides, and are composed of a carboxylic acid group and a hydrocarbon chain of varying carbon lengths and degrees of desaturation. They can be funnelled into various metabolic pathways to synthesise more complex lipid species, including diacylglycerides (DAGs) and triacylglycerides (TAGs), or converted into phosphoglycerides, such as phosphatidic acid (PA), phosphatidylethanolamine (PE) and phosphatidylserine (PS).1 Consequently, FAs contribute to the vast structural diversity of the cellular lipid pool, which in turn serves to regulate several biochemical processes in normal cells. These include synthesis of biological membranes and the modulation of their fluidity, functioning as secondary messengers in signalling pathways to maintain homoeostasis, and serving as a form of energy storage in animals.2 More than 100 years of research have provided tremendous insights into the integral role of FAs in tumorigenesis. Examples include the increased reliance of cancer cells on de novo biosynthesis and exogenous FA uptake to not only sustain their rapid proliferative rate, but also provide an essential energy source during conditions of metabolic stress (Fig. 1).3 In this review, we will explore how cancer cells sustain their FA metabolism in the context of a metabolically dynamic tumour microenvironment, and oncogenic signalling to support tumorigenesis and cancer progression. By considering the interplay of the aforementioned processes, we present opportunities to exploit metabolic dependencies as viable therapeutic options to tackle cancer pathogenesis.

배경

지방산(FAs)은

인산지질, 스핑고지질 및 트리글리세라이드와 같은 여러 지질 종의 주요 구성 요소로,

카르복시산 그룹과 탄소 사슬의 길이와 불포화도가 다양한 탄화수소 사슬로 구성되어 있습니다.

지방산은

더 복잡한 지질 종을 합성하기 위해 다양한 대사 경로로 분배될 수 있으며,

이에는 다이아실글리세라이드(DAGs)와 트리아실글리세라이드(TAGs)가 포함됩니다.

또한 인산글리세라이드(예: 인산화글리세라이드(PA), 인산화에탄올아민(PE), 인산화세린(PS))로

전환될 수 있습니다. 1

따라서

지방산은 세포 지질 풀의 광범위한 구조적 다양성에 기여하며,

이는 정상 세포에서 여러 생화학적 과정을 조절하는 역할을 합니다.

이에는 생물학적 막의 합성 및 유동성 조절,

신호 전달 경로에서 이차 신호 전달체로 기능하여 항상성을 유지하는 것,

동물에서 에너지 저장 형태로 작용하는 것이 포함됩니다.2

100년 이상의 연구는

지방산이 종양 발생에 미치는 필수적인 역할에 대한 엄청난 통찰을 제공했습니다.

예를 들어,

암 세포는

신생 합성과 외부 지방산 섭취에 대한 의존도를 높여

빠른 증식 속도를 유지할 뿐만 아니라

대사 스트레스 조건에서 필수적인 에너지 공급원을 제공합니다(그림 1).3

이 리뷰에서는

대사적으로 동적인 종양 미세환경에서

암 세포가 지방산 대사를 유지하는 메커니즘과 종양 발생 및 암 진행을 지원하는 종양 유발 신호전달 경로를 탐구합니다.

위에서 언급된 과정들의 상호작용을 고려함으로써,

우리는 대사 의존성을 활용하여 암 병리학에 대응할 수 있는 유망한 치료 옵션을 제시합니다.

Fig. 1

Major discoveries in lipid research.

Seminal studies demonstrating the importance of dysregulated fatty acid metabolism in cancer. FASN, fatty acid synthase; SREBPs, sterol regulatory element-binding protein; ACLY, ATP–citrate lyase; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2.

Full size image

How do cancer cells obtain fatty acids?

In mammalian cells, FAs can either be obtained through direct exogenous uptake from the surrounding microenvironment or synthesised de novo by using nutrients, such as glucose or glutamine. It is widely accepted that a metabolic hallmark of cancer cells is lipidomic remodelling, which broadly encompasses alterations in FA transport, de novo lipogenesis, storage as lipid droplets (LDs) and β-oxidation to generate ATP.4 However, the specific mechanisms driving particular lipid phenotypes are nuanced, and may be dependent on tumour type or molecular sub-classifications.

암 세포는 지방산을 어떻게 얻나요?

포유류 세포에서 지방산(FAs)은

주변 미세환경으로부터 직접 외부에서 흡수되거나,

글루코스나 글루타민과 같은 영양소를 사용하여 새롭게 합성될 수 있습니다.

암 세포의 대사적 특징 중 하나로 널리 인정되는 것은 지질체 재편성으로,

이는 지방산 운반, 신규 지방 생합성, 지질 방울(LD)로 저장, ATP 생성을 위한 β-산화 등

다양한 변화를 포괄합니다.4

그러나

특정 지질 표현형을 유발하는 구체적인 메커니즘은 복잡하며,

종양 유형이나 분자 하위 분류에 따라 다를 수 있습니다.

Exogenous uptake of fatty acids allows for metabolic flexibility in cancer cells

In terms of exogenous FA uptake, specialised transporters are required to facilitate efficient movement across the plasma membrane. The most well characterised of these include CD36, also known as fatty acid translocase (FAT), fatty acid transport protein family (FATPs), also known as solute carrier protein family 27 (SLC27) and plasma membrane fatty acid-binding proteins (FABPpm), all of which display increased gene and protein expression‎ in tumours (Fig. 2).5 In particular, high CD36 expression‎ has been correlated with poor prognosis across several tumour types, including breast, ovarian, gastric and prostate.6,7 In the case of highly aggressive Pten−/− prostate cancers, CD36 promotes increased FA uptake and storage in LDs, as well as significant alterations in lipid composition encompassing elevations in acyl-carnitines (ACs), monoacylglycerols (MAGs) and other lysophospholipids, all of which are products of FA oxidation (FAO).8 Notably, deletion of Cd36 is sufficient to rescue the aforementioned phenotypes and mitigate tumour growth, indicating that this FA transporter is integral for promoting the lipidomic remodelling of Pten-deficient prostate cancers.8 Collectively, these findings demonstrate that CD36 plays a key role in tumour microenvironment metabolic crosstalk, ultimately shifting the dependency of tumour cells towards exogenous lipid uptake.

지방산의 외부 섭취는 암 세포의 대사 유연성을 가능하게 합니다

외부 지방산 섭취와 관련하여,

세포막을 통해 효율적으로 이동시키기 위해 특수한 운반체가 필요합니다.

이 중 가장 잘 caractérisé된 것에는

CD36(지방산 운반체, FAT),

지방산 운반 단백질 가족(FATPs, solute carrier protein family 27, SLC27) 및

세포막 지방산 결합 단백질(FABPpm)이 포함되며,

모두 종양에서 유전자 및 단백질 발현이 증가합니다(그림 2). 5 

--> 건강한 정상세포에도 FAT, FATPs, FABPpm이 있는데, 

      암세포에서 지방산 대사를 재프로그래밍해서 활용하는 능력이 증가한다는 뜻!!

특히,

CD36의 높은 발현은

유방, 난소, 위, 전립선 등 여러 종양 유형에서 불량한 예후와 연관되어 있습니다. 6,7 

고도로 공격적인 Pten−/− 전립선 암의 경우,

CD36은 LD 내 지방산(FA)의 흡수 및 저장 증가를 촉진하며,

아실-카르니틴(ACs),

모노아실글리세롤(MAGs) 및 기타 리소포스파티드와 같은 지방산 산화(FAO)의 산물인

지질 구성의 significant한 변화를 유발합니다. 8 

특히, 

Cd36 유전자의 삭제만으로도 앞서 언급된 표현형을 회복시키고

종양 성장 억제를 유도한다는 점은

이 지방산 운반체가 Pten- 결핍 전립선 암의 지질체 재편성에 필수적임을 시사합니다.8 

종합적으로, 이러한 결과는

CD36이 종양 미세환경의 대사 교차작용에서 핵심 역할을 수행하며,

결국 종양 세포의 외부 지방산 섭취 의존성을 전환시킨다는 것을 보여줍니다.

Fig. 2

Cancer cells obtain fatty acids (FAs) from de novo lipogenesis and exogenous uptake.

The exogenous uptake of FAs from the surrounding microenvironment is facilitated by specialised transporters, including CD36, FATPs and FABPpm. FAs and their synthetic products can be subsequently stored as LDs, and used for NADPH and acetyl-CoA production through β-oxidation. In terms of carbon sources for de novo lipogenesis, cancer cells rely on glucose, glutamine and acetate to synthesise citrate. Palmitate is ultimately generated from citrate through the enzymatic activities of ACLY, ACC and FASN, and can subsequently be desaturated and elongated to form a diverse group of lipid species. An alternative pathway for palmitate desaturation exists, which generates sapienate through FADS2, instead of palmitoleate.

Abbreviations: GLUT1, glucose transporter 1; MCT, monocarboxylate transporter; CD36, cluster of differentiation 36; FATPs, fatty acid transport proteins; FABPpm, fatty acid-binding protein; GLS, glutaminase; IDH1/2, isocitrate dehydrogenase; ACLY, ATP–citrate lyase; ACSS2, acyl-CoA synthetase short-chain family member 2; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; SCD, stearoyl-CoA desaturase-1; FADS2, fatty acid desaturase 2; ELOVLs, elongation of very long-chain fatty acid protein; PA, phosphatidic acid; TAG, triacylglycerol; DAG, diacylglycerol; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PS; phosphatidylserine.

암 세포는 지방산(FAs)을 신규 지방 생합성(de novo lipogenesis)과 외부 섭취를 통해 획득합니다.

주변 미세환경으로부터의 FAs 외부 섭취는 

CD36, FATPs 및 FABPpm과 같은 특수 운반체에 의해 촉진됩니다.

 FAs와 그 합성 제품은 이후 지방방울(LDs)로 저장될 수 있으며, 

β-산화 과정을 통해 NADPH와 아세틸-CoA 생산에 사용됩니다. 

신생 지방 생합성의 탄소 원천으로 

암세포는 글루코스, 글루타민, 아세테이트를 활용해 시트르산을 합성합니다. 

시트르산은 ACLY, ACC, FASN 효소의 작용을 통해 팔미테이트로 전환되며, 

이후 불포화 및 연장 과정을 거쳐 다양한 지방 종으로 형성됩니다. 

팔미테이트 불포화화 대안 경로는 

FADS2를 통해 팔미토레이트 대신 

사피엔레이트를 생성합니다. 

약어: GLUT1, 글루코스 운반체 1; MCT, 단일 카르복실산 운반체; CD36, 분화 클러스터 36; FATPs, 지방산 운반 단백질; FABPpm, 지방산 결합 단백질; GLS, 글루타민아제; IDH1/2, 이소시트르산 탈수소효소; ACLY, ATP-시트르산 리아제; ACSS2, 아실-CoA 합성효소 단쇄 가족 구성원 2; ACC, 아세틸-CoA 카복실화효소; FASN, 지방산 합성효소; MUFAs, 단일불포화 지방산; PUFAs, 다중불포화 지방산; SCD, 스테아릴-코엔자임 A 불포화효소-1; FADS2, 지방산 불포화효소 2; ELOVLs, 매우 긴 사슬 지방산 연장 단백질; PA, 인산화 지방산; TAG, 트리아실글리세롤; DAG, 디아실글리세롤; PE, 인산화 에탄올아민; PG, 인산화 글리세롤; PS; 인산화 세린.

따로 탐구) 우리 몸 에너지원의 1~10%를 

                단쇄지방산(아세트산, 뷰티르산, 프로피온산)이 차지함

                그중 아세트산이 60%를 차지함. 뷰티르산, 프로피온산 각각 20%

지난 20년간 위장관(GI)이 식욕 조절에 미치는 영향에 대한 관심이 증가해 왔습니다. 이 중 대부분은 위장관과 뇌 사이의 신경학적 및 호르몬적 관계에 초점이 맞춰져 왔습니다. 최근에는 대장 미생물군과 그들의 대사 활동이 에너지 균형에 중요한 역할을 한다는 증거가 점점 더 쌓이고 있습니다. 대장 미생물군집에 공급되는 기질은 미생물 군집의 구성과 그들이 생성하는 대사산물, 특히 단쇄 지방산(SCFAs)에 큰 영향을 미칩니다. SCFAs는 식이 섬유와 저항성 전분과 같은 소화되지 않는 탄수화물이 대장 미생물군집에 의해 발효될 때 생성됩니다. 발효 가능한 탄수화물의 섭취와 SCFAs의 투여는 체성분 개선, 혈당 균형, 혈중 지질 프로파일 개선, 체중 감소 및 대장암 위험 감소 등 다양한 건강 혜택과 연관되어 보고되었습니다. 그러나 기존 연구들은 발효 가능한 탄수화물과 SCFAs가 특정 조직과 대사 과정에 미치는 영향을 보고하는 데 집중되어 있으며, 이러한 국소적 효과가 어떻게 체계적 효과로 전환되어 질병 위험을 완화하는지 설명하지 못하고 있습니다. 또한 연구들은 SCFAs를 집단적으로 조사하고 개별 SCFAs와 관련된 효과를 보고하지 않는 경향이 있습니다. 본 연구에서는 최근 증거를 종합하여 SCFAs의 유익한 측면 중 하나인 식욕 조절과 에너지 균형에 대한 SCFAs의 효과를 설명하는 포괄적인 모델을 제안합니다.

An intriguing observation during the metastatic dissemination of breast, prostate and ovarian cancer cells is their preferential homing to adipocyte tissue located in periglandular regions and the visceral omentum.9 It has long been appreciated that adipose tissue is implicated in metabolic syndromes such as obesity, and functions as an endocrine system that secretes growth factors, cytokines and free FAs following lipolysis.10 In this respect, co-culture, as opposed to isolated, cell systems have been instrumental in our understanding of the impact of adipocytes on the FA metabolism of cancer cells.11 Importantly, these seminal studies have demonstrated that the migration and proliferation of human ovarian cancer cells are significantly increased following co-culture either directly with human-derived omentum adipocytes, or their conditioned media.11 In these models, adipocytes were shown to activate endogenous lipolysis of triglycerides to produce free FAs that could be subsequently secreted and taken up by metastatic cells overexpressing FABP4.11 The transfer of FAs from surrounding adipocytes to metastatic ovarian cancer cells also potentiated AMP-activated protein kinase (AMPK) signalling in the latter, culminating in increased β-oxidation through carnitine palmitoyltransferase 1 (CPT1) and acyl-CoA oxidase 1 activation.11 The overexpression‎ of the FA translocase CD36 is also essential for driving the progression of ovarian cancer, and this is largely mediated through rapid exogenous uptake of long-chain FAs and cholesterol that likewise, are obtained from the adipocytes in the microenvironment.7

A major implication of elevated uptake of exogenous FAs is their subsequent storage in LDs, which are cytoplasmic organelles that sequester excess FAs in the form of TAGs and sterol esters.12 Consequently, the accumulation of LDs in cancer cells is used not only to maintain lipid homoeostasis and prevent lipotoxicity, but also to provide a valuable source of ATP and NADPH during conditions of metabolic stress (Fig. 2).12,13 This is largely achieved through β-oxidation of stored lipids, leading to the production of acetyl-CoA through oxidative degradation of FAs.14,15 The acetyl-CoA produced from each round of β-oxidation can subsequently enter the tricarboxylic acid (TCA) cycle to generate NADH and FADH2 for the electron transport chain, ultimately leading to the synthesis of approximately six times more ATP than oxidation of carbohydrates.14 Moreover, the oxidation of citrate derived from acetyl-CoA by isocitrate dehydrogenase 1 (IDH1) is one of the main sources of cellular NADPH production.16 Thus, β-oxidation of LDs provides sufficient ATP to fuel the metastatic cascade, and generates NADPH that is essential for anabolic metabolism and detoxification of reactive oxygen species (ROS).17,18,19,20 This is particularly relevant for hypoxic cells, which have elevated FA uptake and accumulation of LDs following hypoxia-inducible factor (HIF)-1α-dependent expression‎ of FABP3 and FABP7.21 The oxidation of triglycerides stored in LDs provides sufficient ATP to facilitate the recovery of breast cancer and glioblastoma cells during reoxygenation, whilst the increase in NADPH levels serves to protect against ROS toxicity.21 Indeed, knockdown of FABP3 and FABP7 decreases the growth of U87 glioblastoma tumours in vivo, an effect largely attributable to reduced FA uptake and inhibition of LD formation.21

On a broader level, delineating the mechanisms driving interactions between cancer cells and adipocytes has provided fundamental insights into how obesity contributes to tumour initiation and progression. This is particularly relevant for renal, gastric, breast and colon cancers that preferentially grow in adipocyte-rich environments.10 It is noteworthy that adipose tissue associated with obesity recapitulates a state of persistent inflammation characterised by the secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, as well as production of vascular endothelial growth factor (VEGF), prostaglandins and leukotrienes by activated macrophages.22 Thus, adipose cells can function as active mediators of endocrine and paracrine signalling, which in turn support the crosstalk between adiposity and cancer cell FA metabolism.23 Indeed, this reciprocal crosstalk perpetuates an interaction network in which secreted adipokines stimulate cancer cells to release exosomes containing pro-lipolytic factors such as miRNA-144 and miRNA-126, which in turn promote lipolysis in adjacent adipocytes through activation of AMPK signalling and induction of autophagy.9,24 Ultimately, enhanced lipolysis and release of free FAs fundamentally alters the metabolic dependencies of migrating cancer cells, shifting their reliance towards exogenous lipid uptake and β-oxidation for energy supply.24,25 These findings also point to a rationale for developing therapies targeting the tumour microenvironment through inhibition of adipocyte lipolysis, thereby reducing the availability of free lipids for cancer cells.26

The uptake and scavenging of extracellular FAs also provides an important compensatory mechanism for cancer cells to sustain their lipid demands under conditions of metabolic stress. For instance, the flux from glucose to acetyl-CoA decreases under hypoxic conditions, and so does the conversion of saturated FAs into monounsaturated FAs, as it is regulated by the oxygen-consuming enzyme stearoyl-CoA desaturase-1 (SCD-1). Consequently, hypoxic cells display increased uptake of exogenous lysophospholipids, such as lysophosphatidylcholine (LPC), in order to sustain their proliferation and survival.27 The regulation of exogenous lipid uptake under hypoxia largely occurs through the HIF-dependent overexpression‎ of lipid-binding proteins. For instance, FABP4 is a transcriptional target of HIF1α that facilitates extracellular scavenging of long-chain unsaturated lysophospholipids, including LPCs, lysophosphatidylethanolamines (LPEs) and lysophosphatidylglycerols (LPGs) that can be used as a nutrient source under conditions of metabolic stress.27,28 Interestingly, this phenotype of increased FA scavenging is also recapitulated under normoxic conditions following oncogenic Ras activation, and is accompanied by reduced oxygen consumption, elevated citrate synthesis from reductive carboxylation and a consequent independence from SCD-1 to derive unsaturated FAs.27 Taken together, these results demonstrate that whilst changes in the microenvironment conditions or oncogenic activation of signalling pathways confer resistance to SCD-1 inhibitors, they might open novel opportunities for therapy by increasing the reliance of cancer cells on FA uptake.

유방암, 전립선암 및 난소암 세포의 전이 확산 과정에서 흥미로운 관찰 결과는

이들이 주변 선조직과 내장 장막에 위치한 지방세포 조직으로 선호적으로 이동한다는 점입니다.9

지방 조직은 비만과 같은 대사 증후군과 연관되어 있으며,

지방 분해 후 성장 인자, 사이토킨 및 자유 지방산을 분비하는 내분비 시스템으로 기능한다는 것이

오래전부터 알려져 있습니다. 10

이 점에서,

분리된 세포 시스템이 아닌 공배양 시스템은

지방세포가 암 세포의 지방산 대사에게 미치는 영향을 이해하는 데

결정적인 역할을 했습니다.11

특히, 이 선구적인 연구들은

인간 난소 암 세포의 이동 및 증식이

인간 유래 장막 지방세포와 직접 공배양하거나

그 배양액과 공배양한 후 유의미하게 증가함을 보여주었습니다. 11

이 모델에서 지방세포는

내인성 트리글리세라이드 분해를 활성화하여 자유 지방산을 생성하며,

이는 이후 FABP4 과발현을 보이는 전이성 세포에 분비되어 흡수되었습니다. 11

주변 지방세포로부터 전이성 난소암 세포로의 지방산 전달은

후자의 AMP 활성화 단백질 키나제(AMPK) 신호전달을 강화하여

카르니틴 팔미토일트랜스퍼레이스 1(CPT1) 및

아실-코엔자임 A 산화효소 1 활성화로 이어져 β

-산화 증가를 초래했습니다. 11

지방산 운반체 CD36의 과발현은

난소암의 진행을 촉진하는 데 필수적이며,

이는 주로 미세환경의 지방세포에서 유래한 장쇄 지방산과

콜레스테롤의 빠른 외인성 흡수를 통해 매개됩니다.7

외인성 지방산의 증가된 흡수의 주요 함의는

이들이 이후 LD에 저장된다는 점입니다.

LD는

과잉 지방산을 트리글리세라이드(TAG)와 스테롤 에스터 형태로 격리하는

세포질 소기관입니다. 12

따라서

암 세포 내 LD의 축적은

지질 균형 유지와 지질 독성 예방뿐만 아니라

대사 스트레스 조건 하에서 ATP와 NADPH의 중요한 공급원으로 활용됩니다(그림 2).12,13

이는

저장된 지질의 β-산화 과정을 통해 지방산의 산화 분해로

아세틸-CoA를 생성하는 방식으로 주로 이루어집니다. 14,15

β-산화 각 단계에서 생성된 아세틸-CoA는

트리카르복실산(TCA) 회로에 진입해 전자 전달 사슬에 필요한 NADH와 FADH2를 생성하며,

이는 탄수화물 산화보다 약 6배 더 많은 ATP 합성을 최종적으로 이끌어냅니다. 14

또한

아세틸-CoA에서 유래한 시트르산이 이소시트르산 탈수소효소 1(IDH1)에 의해 산화되는 과정은

세포 내 NADPH 생산의 주요 원천 중 하나입니다. 16

따라서

LD의 β-산화는

전이 연쇄를 유지하기에 충분한 ATP를 공급하며,

반응성 산소 종(ROS)의 해독과 동화 대사 과정에 필수적인 NADPH를 생성합니다.17,18,19,20

이는 특히

저산소 환경에서 저산소 유도 인자(HIF)-1α에 의존적으로 FABP3 및 FABP7 발현이 증가함에 따라

지방산(FA) 흡수 및 LD 축적이 증가하는 저산소 세포에 특히 중요합니다. 21

LD에 저장된 트리글리세라이드의 산화는

재산소화 과정에서 유방암 및 글리오blastoma 세포의 회복을 촉진하기 위해 충분한 ATP를 공급하며,

NADPH 수준 증가가 ROS 독성으로부터 보호하는 역할을 합니다.21

실제로,

FABP3 및 FABP7의 발현을 억제하면 U87 글리오blastoma 종양의 성장 속도가 감소하며,

이는 주로 지방산 흡수 감소와 LD 형성 억제에 기인합니다.21

더 넓은 맥락에서,

암 세포와 지방 세포 간의 상호작용을 조절하는 메커니즘을 규명하는 것은

비만이 종양 발생 및 진행에 어떻게 기여하는지에 대한 근본적인 통찰을 제공했습니다.

이는 특히

지방세포가 풍부한 환경에서

선호적으로 성장하는 신장, 위, 유방 및 대장 암에 특히 관련이 있습니다.10

비만과 관련된 지방 조직은

활성화된 대식세포에 의해

종양 괴사 인자 (TNF)-α, 인터루킨 (IL)-6 및 IL-8의 분비, 혈관 내피 성장 인자 (VEGF),

프로스타글란딘 및 류코트리엔의 생산을 특징으로 하는

지속적인 염증 상태를 재현합니다. 22

따라서

지방 세포는 내분비 및 파라크린 신호 전달의 활성 매개체로 기능하며,

이는 지방량과 암 세포의 지방산 대사 사이의 교차 작용을 지원합니다. 23

실제로, 이러한 상호 교차 작용은

분비된 아디포키인이 암세포를 자극하여

miRNA-144 및 miRNA-126과 같은 지방 분해 인자를 포함하는 엑소좀을 방출하도록 하는

상호 작용 네트워크를 지속시킵니다.

이 엑소좀은

AMPK 신호 전달을 활성화하고

자가포식을 유도하여

인접한 지방세포에서 지방 분해를 촉진합니다. 9,24

궁극적으로 강화된 지방 분해와 자유 지방산의 방출은

이동 중인 암 세포의 대사 의존성을 근본적으로 변화시켜,

에너지 공급을 위해 외인성 지방 섭취와 β-산화 의존도로 전환시킵니다.24,25

이러한 결과는

지방세포의 지방 분해를 억제하여 암 세포에 공급되는 자유 지방산의 가용성을 감소시키는 방식으로

종양 미세환경을 표적으로 하는 치료법 개발의 근거를 제시합니다.26

세포외 지방산의 흡수 및 제거는

대사 스트레스 조건 하에서

암 세포의 지방 요구량을 유지하기 위한 중요한 보상 메커니즘을 제공합니다.

예를 들어,

저산소 조건에서 포도당에서 아세틸-CoA로의 유동량이 감소하며,

산소 소비 효소인 스테아로일-CoA 탈수소효소-1(SCD-1)에 의해 조절되는

포화 지방산의 단일불포화 지방산으로의 전환도 감소합니다.

결과적으로

저산소 세포는

증식 및 생존을 유지하기 위해 외인성 리소포스파티드콜린(LPC)과 같은

리소포스파티드지질을 증가시켜 흡수합니다.27

저산소 조건 하에서 외인성 지질 흡수의 조절은

주로 HIF 의존적 지질 결합 단백질의 과발현을 통해 이루어집니다.

예를 들어,

FABP4는 HIF1α의 전사적 표적으로,

대사 스트레스 조건에서 영양소원으로 활용될 수 있는

장쇄 불포화 리소포스파티드 지질(LPC, LPEs, LPGs)의 세포외 흡수 촉진 역할을 합니다. 27,28

흥미롭게도,

이 지방산 수집 증가 현상은

종양 유발 Ras 활성화 후 정상 산소 조건에서도 재현되며,

산소 소비 감소, 환원성 카복실화로부터의 시트르산 합성 증가,

그리고 불포화 지방산을 얻기 위해 SCD-1에 대한 의존성 감소와 동반됩니다. 27

종합적으로, 이러한 결과는

미세환경 조건의 변화나 종양 유발 신호 전달 경로의 활성화가 SCD-1 억제제에 대한 저항성을 부여하지만,

암 세포의 지방산 흡수 의존도를 증가시켜

새로운 치료 기회를 열어줄 수 있음을 보여줍니다.

De novo lipogenesis allows for the synthesis of a diverse group of fatty acids

De novo lipogenesis is the process through which carbon atoms derived from carbohydrates such as glucose and amino acids including glutamine are converted into FAs.29 In normal tissue, de novo lipogenesis is restricted to hepatocytes and adipocytes; however, cancer cells may also reactivate this anabolic pathway even in the presence of exogenous lipid sources.3,30 The main substrate for FA synthesis is cytoplasmic acetyl-CoA that can either be derived from citrate or acetate.3 Carbons from glucose or glutamine contribute to citrate production either from the oxidation of pyruvate in the TCA cycle or through reductive carboxylation, respectively.31,32 In addition, under conditions of metabolic stress such as hypoxia or lipid depletion, cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2) in order to generate acetyl-CoA from acetate.33 Citrate is converted into acetyl-CoA by ATP–citrate lyase (ACLY), which is the substrate for the carboxylating enzymes acetyl-CoA carboxylases (ACCs).26,34 The irreversible carboxylation of acetyl-CoA into malonyl-CoA is the rate-limiting step of de novo lipogenesis, and it is the condensation of seven malonyl-CoA molecules and one molecule of acetyl-CoA catalysed by fatty acid synthase (FASN), which ultimately produces the saturated 16-carbon FA palmitate (FA16:0).26,35 Subsequent desaturation of palmitate by stearoyl-CoA desaturase (SCD) produces monounsaturated FAs with a double bond at position Δ9, whilst elongation by FA elongases, such as ELOVL6, adds two-carbon groups to palmitate in order to form the saturated FA stearate (Fig. 2).26,36,37

The regulation of de novo lipogenesis occurs largely at the transcriptional level through the activation of sterol regulatory element-binding proteins (SREBPs), of which three main transcription factors exist: SREBP1a and SREBP1c arising from the alternative splicing of SREBPF1, and SREBP2 encoded by the SREBPF2 gene.38 SREBPs are initially found as inactive 125-kDa precursors, bound to the endoplasmic reticulum (ER). At saturated concentrations of intracellular cholesterol, insulin-induced genes (INSIGs) bind to SREBP-cleavage-activating proteins (SCAPs) and localise the SREBP precursors to the ER.39,40 Conversely, under conditions of low cholesterol levels, SCAPs facilitate the translocation of ER-bound SREBPs to the Golgi, where the transcription factor is subsequently cleaved by membrane-bound transcription factor site 1 proteases (MBTPS1 and MBPTS2) to release the active N terminus.41,42 Ultimately, it is the N-terminal fragment that translocates to the nucleus and induces the transcription of genes containing sterol regulatory elements (SREs), such as FASN, ACLY and ACC.26,43,44

One of the main advantages for cancer cells to sustain higher de novo lipogenesis of FAs is their flexibility to shunt them into different biosynthetic pathways to generate a diverse cellular pool of lipid species with distinct functions. Indeed, upregulation of lipid synthesis, followed by downstream elongation and desaturation pathways, has been shown to be sufficient to produce all FAs from the nutrients, such as glucose, glutamine and acetate, which are required for adipocyte differentiation.45 Palmitate (FA16:0) is the main product of de novo lipogenesis, and can be elongated and desaturated through the activity of SCD, ELOVLs and FADs to produce additional FA species including stearate (FA18:0) and oleate (FA18:1) (Fig. 2).46 These FAs can be subsequently used for the production of more complex lipids. Notably, oleate can directly feed into PA synthesis through the enzymatic activities of glycerol-3-phosphate acyltransferase 1 (GPAT1) and acyl-CoA:LPA acyltransferase (LPAT), as well as being incorporated into TAGs for storage in a GPAT1-dependent fashion.47,48,49 With respect to PA, this class of phospholipid not only serves important structural and signalling roles, but is also one of the main substrates for DAG synthesis by Lipin1–3 and AGPAT, as well as contributing to the biosynthesis of complex glycerolipids.50,51 For instance, PA can be condensed with CTP through a reaction catalysed by CDP–DAG synthase (CDS) to generate CDP–DAG.52,53 Importantly, CDP–DAG is the main precursor for the de novo synthesis of complex glycerolipids including phosphatidylinositols (PtdIns), phosphatidylserines (PSs), phosphatidylglycerols (PGs) and phosphatidylcholines (PCs) (Fig. 2).54

More recently, studies have begun to elucidate the various compensatory pathways implicated in FA metabolism that cancer cells exploit to increase their adaptability. This has been most extensively studied with the SCD enzymes, which were previously thought to be the only desaturases that generate monounsaturated FAs from palmitate. SCDs are necessary for tumorigenesis as they regulate the cellular pool of unsaturated FAs that later serve as building blocks for phosphoglycerides, phosphoinositides, eicosanoids and sphingolipids. As a result, they constitute an attractive target for therapeutic intervention; however, inhibitors targeting these metabolic enzymes have only shown modest effects.55,56 This suggests that cancer cells may rely on alternative desaturation pathways to generate functionally useful lipid species, thus relieving their dependence on canonical SCD-mediated desaturation. Indeed, FADS2 has been shown to play a dominant role in FA desaturation in cancer cell lines and primary tumours that are resistant to SCD inhibitors.57 Of note, these cells exploit an alternative pathway involving the FADS2-dependent desaturation of palmitate to sapienate (cis-6-C16:1) to support their membrane synthesis during proliferation.57

신생 지방생성은 다양한 지방산 그룹의 합성을 가능하게 합니다

신생 지방생성은 탄수화물(예: 글루코스) 및 아미노산(예: 글루타민)에서 유래한 탄소 원자가 지방산(FAs)으로 전환되는 과정입니다.29 정상 조직에서는 신생 지방생성이 간세포와 지방세포에 제한되지만, 암 세포는 외부 지방 공급원이 존재하더라도 이 동화 경로를 재활성화할 수 있습니다. 3,30 지방산 합성의 주요 기질은 시트르산 또는 아세테이트에서 유래할 수 있는 세포질 아세틸-코엔자임 A입니다.3 포도당이나 글루타민에서 유래한 탄소 원자는 각각 TCA 회로의 피루vate 산화 또는 환원적 카복실화 과정을 통해 시트르산 생성에 기여합니다. 31,32 또한 저산소증이나 지방 고갈과 같은 대사 스트레스 조건에서 암 세포는 아세틸-코엔자임 A 합성효소 2(ACSS2)를 상향 조절하여 아세테이트로부터 아세틸-코엔자임 A를 생성합니다.33 시트르산은 ATP-시트르산 리아제(ACLY)에 의해 아세틸-코엔자임 A로 전환되며, 이는 아세틸-코엔자임 A 카복실화 효소(ACCs)의 기질입니다. 26,34 아세틸-CoA의 말론일-CoA로의 불가역적 카복실화는 신생 지방 생합성의 속도 제한 단계이며, 이는 지방산 합성효소(FASN)에 의해 촉매되는 7분자의 말론일-CoA와 1분자의 아세틸-CoA의 축합 반응으로, 최종적으로 포화 16탄소 지방산인 팔미테이트(FA16:0)를 생성합니다. 26,35 팔미테이트는 스테아릴-코엔자임 A 탈포화효소(SCD)에 의해 불포화되어 Δ9 위치에 이중 결합을 가진 단일 불포화 지방산을 생성하며, 지방산 연장효소(예: ELOVL6)에 의한 연장 과정은 팔미테이트에 2탄소 그룹을 추가하여 포화 지방산인 스테아레이트(FA16:0)를 형성합니다(그림 2).26,36,37

신생 지방 생합성의 조절은 주로 스테롤 조절 요소 결합 단백질(SREBPs)의 활성화에 의해 전사 수준에서 이루어지며, 이 중 세 가지 주요 전사 인자가 존재합니다: SREBP1a와 SREBP1c는 SREBPF1 유전자의 대안적 스플라이싱에서 유래하며, SREBP2는 SREBPF2 유전자에 의해编码됩니다.38 SREBPs는 초기에는 비활성 상태의 125-kDa 전구체로 내소체(ER)에 결합된 형태로 존재합니다. 세포 내 콜레스테롤 농도가 포화 상태에 이르렀을 때, 인슐린 유도 유전자(INSIGs)는 SREBP 분해 활성화 단백질(SCAPs)에 결합하여 SREBP 전구체를 ER로 국소화합니다. 39,40 반면, 콜레스테롤 농도가 낮은 조건에서는 SCAPs가 ER에 결합된 SREBPs의 골지체로의 이동을 촉진하며, 여기서 전사 인자는 막 결합형 전사 인자 사이트 1 프로테아제(MBTPS1 및 MBPTS2)에 의해 절단되어 활성 N 말단이 방출됩니다. 41,42 최종적으로 N-말단 조각이 핵으로 이동하여 스테롤 조절 요소(SRE)를 포함하는 유전자(예: FASN, ACLY 및 ACC)의 전사를 유도합니다.26,43,44

암 세포가 지방산(FAs)의 신생합성을 높게 유지하는 주요 장점 중 하나는 이를 다양한 생합성 경로로 분배하여 기능이 다른 다양한 세포 내 지방산 종을 생성할 수 있는 유연성입니다. 실제로 지방산 합성의 증가에 이어 하류의 연장 및 불포화 경로가 활성화되면, 글루코스, 글루타민, 아세테이트와 같은 영양소로부터 모든 지방산을 생성하는 것이 입증되었습니다. 45 팔미테이트(FA16:0)는 신규 지방 생합성의 주요 제품으로, SCD, ELOVL 및 FAD의 활성을 통해 연장 및 불포화되어 스테아레이트(FA18:0)와 올레이트(FA18:1)와 같은 추가 지방산 종을 생성할 수 있습니다(그림 2).46 이러한 지방산은 이후 더 복잡한 지질의 생산에 사용될 수 있습니다. 특히 올레산은 글리세롤-3-인산 아실트랜스퍼레이즈 1(GPAT1)과 아실-CoA:LPA 아실트랜스퍼레이즈(LPAT)의 효소 활성을 통해 PA 합성에 직접 공급될 수 있으며, GPAT1에 의존적인 방식으로 TAG에 저장되기도 합니다. 47,48,49 PA는 구조적 및 신호 전달 역할을 수행하는 것 외에도 Lipin1–3 및 AGPAT에 의해 DAG 합성의 주요 기질로 작용하며, 복잡한 글리세롤지질의 생합성에 기여합니다. 50,51 예를 들어, PA는 CDP–DAG 합성효소(CDS)에 의해 촉매되는 반응을 통해 CTP와 응축되어 CDP–DAG를 생성합니다. 52,53 특히, CDP–DAG는 포스파티딜리노시톨(PtdIns), 포스파티딜세린(PSs), 포스파티딜글리세롤(PGs) 및 포스파티딜콜린(PCs)을 포함한 복잡한 글리세롤리피드의 신규 합성의 주요 전구체입니다(그림 2).54

최근 연구에서는 암 세포가 적응력을 높이기 위해 활용하는 지방산 대사 관련 다양한 보상 경로가 밝혀지기 시작했습니다. 이 중 SCD 효소는 이전에 팔미테이트로부터 단일불포화 지방산을 생성하는 유일한 불포화효소로 여겨졌지만, 최근 연구에서 이 효소가 지방산 대사에서 중요한 역할을 한다는 것이 밝혀졌습니다. SCD는 세포 내 불포화 지방산의 풀을 조절하여 이후 인산글리세리드, 인산인오시타이드, 에이코사노이드 및 스핑고지질의 구성 요소로 사용되기 때문에 종양 발생에 필수적입니다. 이로 인해 이들은 치료적 개입의 유망한 표적이 되었으나, 이러한 대사 효소를 표적으로 하는 억제제는 제한된 효과를 보였습니다.55,56 이는 암 세포가 기능적으로 유용한 지질 종을 생성하기 위해 SCD 매개 불포화 경로에 의존하지 않고 대체 불포화 경로를 활용할 수 있음을 시사합니다. 실제로 FADS2는 SCD 억제제에 내성을 보이는 암 세포주 및 원발성 종양에서 지방산 불포화 반응에 주요 역할을 하는 것으로 밝혀졌습니다.57 주목할 점은 이러한 세포가 증식 과정에서 막 합성을 지원하기 위해 FADS2에 의존하는 팔미테이트에서 사피에네이트(cis-6-C16:1)로의 불포화 반응을 포함한 대체 경로를 활용한다는 것입니다.57

The context-dependent regulation of lipid metabolism: convergence of molecular heterogeneity and oncogenic signalling

Several metabolic processes in cancer cells are directly regulated by oncogenes and tumour suppressors. For instance, mutant KRAS enhances glycolysis in pancreatic cancer cells through upregulation of the genes encoding hexokinase 1/2 (Hk1 and Hk2, respectively), and redirects glutamine flux to malate for the production of pyruvate and reducing power in the form of NADPH.58,59 Moreover, amplification of the MYC oncogene drives increased glutamine metabolism and anaplerosis by transcriptionally activating mitochondrial glutaminase (GLS1) and the SLC1A5 glutamine transporter.60,61 Hyperactivation of the phosphoinositide 3-kinase and AKT (PI3K–AKT) pathway has also been implicated in the rewiring of specific metabolic processes, including increased glucose uptake through stabilisation of glucose transporter 1 (GLUT1), enhanced glutamine anaplerosis via activation of glutamate pyruvate transaminase 2 (GPT2) and remodelling of the cellular lipidome.62,63,64 It is also becoming increasingly appreciated that the complex regulatory networks involved in FA metabolism must be considered in specific molecular and metabolic contexts. These include the impact of molecular heterogeneity, as exemplified by the intrinsic subtypes of breast cancer, as well as the oncogenic processes that drive malignant transformation in different cancers.

지질 대사 조절의 맥락 의존성: 분자적 이질성과 종양 유발 신호전달의 수렴

암 세포의 여러 대사 과정은 종양 유전자와 종양 억제자에 의해 직접 조절됩니다. 예를 들어, 돌연변이 KRAS는 췌장암 세포에서 헥소키나제 1/2(Hk1 및 Hk2)를编码하는 유전자의 발현을 증가시켜 글리코lysis를 촉진하며, 글루타민 유동을 말산으로 재분배하여 피루vate와 NADPH 형태의 환원력을 생산합니다. 58,59 또한 MYC 발암 유전자의 증폭은 미토콘드리아 글루타민아제(GLS1)와 SLC1A5 글루타민 운반체의 전사 활성화를 통해 글루타민 대사 및 아나플로로시스를 증가시킵니다. 60,61 인산인오시타이드 3-키나제(PI3K) 및 AKT(PI3K–AKT) 경로의 과활성화는 특정 대사 과정의 재편성에 관여하며, 이는 글루코스 운반체 1(GLUT1)의 안정화를 통해 글루코스 흡수 증가, 글루타메이트 피루베이트 트랜스아미나제 2(GPT2) 활성화로 인한 글루타민 아나플로시스 강화, 세포 지질체 재편성 등을 포함합니다. 62,63,64 지방산 대사 관련 복잡한 조절 네트워크는 특정 분자적 및 대사적 맥락에서 고려되어야 한다는 점이 점점 더 인정받고 있습니다. 이는 유방암의 내재적 하위 유형과 같은 분자적 이질성의 영향뿐만 아니라 다양한 암에서 악성 변형을 촉진하는 종양 발생 과정도 포함됩니다.

Molecular heterogeneity and lipid reprogramming

Gene expression‎ analyses have long suggested that upregulation of several enzymes involved in lipid metabolism is a near-universal metabolic hallmark of cancer cells.4,65 However, more nuanced observations from these genomic studies highlight differences in the expression‎ of lipid enzymes across different tumour types and molecular sub-classifications.4 For instance, long-chain acyl-CoA synthetase 3 (ACSL3) is overexpressed in androgen-dependent cancers, such as prostate tumours, where it activates cholesterol synthesis and steroidogenesis, but it is downregulated in triple-negative breast cancers.66,67 Furthermore, enzymes involved in β-oxidation such as α-methylacyl-CoA racemase (AMACR) and CPT1B are specifically overexpressed in colorectal, hepatic and prostate cancers, whilst CPT1A is upregulated in breast cancer.4,68 The upregulation of AMACR in prostate cancer is highly significant to the extent that it is used as a bona fide biomarker for early detection and diagnosis of prostate cancer.68 Furthermore, it also suggests that β-oxidation, particularly of branched-chain FAs, is the main bioenergetic pathway for obtaining ATP and NADPH in prostate cancer cells.69 Clinically, prostate cancers display low rates of glycolysis, and are therefore poor candidates for diagnostic imaging by using fludeoxyglucose positron emission tomography (FDG-PET).70 The higher dependence on FAO could serve as an alternative metabolic signature for prostate cancer diagnosis, and indeed this dependency is currently being explored as a novel imaging application through the use of C11-acetate PET tracers.70 Thus, although dysregulated lipid metabolism is a broad feature of cancer, different tumour types may exhibit unique metabolic adaptations that contribute to the remodelling of their lipidome.

The regulatory complexity of lipid metabolism in the context of molecular heterogeneity is perhaps best exemplified in breast cancer, which comprises multiple different subtypes characterised by unique hormone/growth-factor receptor expression‎ and genetic profiles.71 Comparative mRNA expression‎ analyses between receptor-positive and triple-negative breast cancers (RPBC and TNBC, respectively) have revealed notable differences between these subtypes in terms of lipid procurement, storage and oxidation.4 Interestingly, RPBCs are associated with a gene signature encompassing elevated de novo lipogenesis, FA mobilisation and oxidation, whilst TNBCs overexpress genes involved in exogenous lipid uptake – including FABP5 and FABP7 – and storage.4 It is also notable that TNBCs are dependent on different ACSL isoforms when compared with RPBCs to mobilise FAs that have been stored in LDs.4 Specifically, overexpression‎ of ACSL4 in TNBCs is associated with the enhanced metabolism of arachidonic acid to arachidonyl-CoA that can be used as a substrate for cyclo-oxygenase 2 (COX2) for prostaglandin synthesis.4 The co-ordinated synthesis of pro-inflammatory prostaglandins from LDs may, in turn, contribute to the more aggressive phenotypes generally observed in TNBCs compared with RPBCs.4,72

Although gene expression‎ analyses may not necessarily provide a direct reflection of enzyme activity or dependencies on specific metabolic pathways, studies have validated unique lipid-associated genetic signatures that can be used to guide therapeutic intervention.67,73 For instance, a subset of TNBCs with MYC overexpression‎ have been shown to upregulate several genes involved in β-oxidation, such as PGC1α, CPT1B and CDCP1, whilst downregulating FASN and ACACB.73 Importantly, a genetic signature associated with FAO contributes to the aggressiveness and poor clinical outcome of MYC-high TNBCs, suggesting that it is an essential bioenergetics pathway of these tumours.73 Indeed, inhibition of CPT1 and consequently FAO with etomoxir significantly reduces the primary tumour growth of MYC-high, but not MYC-low, TNBCs or RPBCs.73 The potential to exploit the metabolic dependency of TNBCs on β-oxidation has also been demonstrated for the treatment of metastatic disease, with the inhibition of CUB-domain-containing protein 1 (CDCP1) significantly impairing the capacity of TNBCs to oxidise FAs stored in LDs during migration and metastasis.67 Overall, rather than considering dysregulated lipid homoeostasis as a general feature of cancer cells, it is important to understand the molecular subtype, tissue and the overall tumour microenvironment context of such changes. This will undoubtedly lead to better stratification methods and targeted application of metabolic inhibitors that block specific pathways involved in lipid metabolism.

분자적 이질성과 지질 재프로그래밍

유전자 발현 분석은 오랫동안 지질 대사 관련 여러 효소의 발현 증가가 암 세포의 거의 보편적인 대사적 특징임을 제시해 왔습니다.4,65 그러나 이러한 유전체 연구에서 얻어진 더 세분화된 관찰 결과는 다양한 암 유형과 분자적 하위 분류에 따라 지질 효소의 발현에 차이가 있음을 강조합니다. 4 예를 들어, 장쇄 아실-코엔자임 A 합성효소 3(ACSL3)는 안드로겐 의존성 암인 전립선 종양에서 콜레스테롤 합성과 스테로이드 생성을 활성화하지만, 삼중 음성 유방암에서는 발현이 감소됩니다. 66,67 또한, β-산화 관련 효소인 α-메틸아실-CoA 라세마제(AMACR)와 CPT1B는 대장암, 간암, 전립선암에서 특이적으로 과발현되며, CPT1A는 유방암에서 발현이 증가합니다.4,68 전립선암에서의 AMACR 발현 증가가 매우 유의미하여 전립선암의 조기 진단 및 검출을 위한 진정한 바이오마커로 사용됩니다. 68 또한, β-산화, 특히 분지쇄 지방산의 β-산화가 전립선 암 세포에서 ATP와 NADPH를 생성하는 주요 생체 에너지 경로임을 시사합니다.69 임상적으로 전립선 암은 글리코lysis율이 낮아 플루데옥시글루코스 양전자 방출 단층 촬영(FDG-PET)을 이용한 진단 영상 검사에 적합하지 않습니다. 70 지방산 대사(FAO)에 대한 높은 의존도는 전립선 암 진단 위한 대체 대사적 지표로 활용될 수 있으며, 실제로 이 의존도는 C11-아세테이트 PET 추적제를 활용한 새로운 영상 응용 기술로 현재 탐구 중입니다.70 따라서, 지질 대사 장애는 암의 광범위한 특징이지만, 다양한 종양 유형은 지질체 재편성에 기여하는 독특한 대사적 적응을 나타낼 수 있습니다.

분자적 이질성 맥락에서 지질 대사 조절의 복잡성은 유방암에서 가장 잘 보여집니다. 유방암은 호르몬/성장 인자 수용체 발현과 유전적 프로파일에서 독특한 특징을 가진 여러 다른 하위 유형으로 구성됩니다.71 수용체 양성 유방암(RPBC)과 삼중 음성 유방암(TNBC) 간의 비교 mRNA 발현 분석은 이 하위 유형 간 지질 획득, 저장 및 산화 측면에서 눈에 띄는 차이를 드러냈습니다. 4 흥미롭게도 RPBC는 신규 지질 생합성, 지방산 동원 및 산화 증가를 포함하는 유전자 서명을 나타내며, TNBC는 외인성 지질 흡수(FABP5 및 FABP7 포함) 및 저장 관련 유전자의 과발현을 보입니다.4 또한 TNBC는 RPBC와 비교할 때 LD에 저장된 지방산을 동원하기 위해 다른 ACSL 이소형에 의존한다는 점도 주목할 만합니다. 4 구체적으로, TNBC에서 ACSL4의 과발현은 아라키돈산이 아라키돈일-CoA로 대사되는 과정이 강화되며, 이는 프로스타글란딘 합성에 사용되는 사이클로옥시게나제 2(COX2)의 기질로 활용될 수 있습니다. 4 LD에서 프로염증성 프로스타글란딘의 조화된 합성은, 차례로, RPBC와 비교할 때 TNBC에서 일반적으로 관찰되는 더 공격적인 표현형에 기여할 수 있습니다.4,72

유전자 발현 분석은 반드시 효소 활성이나 특정 대사 경로에 대한 의존성을 직접 반영하지는 않지만, 치료적 개입을 안내하기 위해 활용될 수 있는 독특한 지질 관련 유전적 특성을 검증한 연구들이 있습니다.67,73 예를 들어, MYC 과발현을 보이는 TNBC의 일부 하위 그룹은 β-산화 관련 유전자인 PGC1α, CPT1B 및 CDCP1을 상향 조절하며, FASN과 ACACB를 하향 조절하는 것으로 나타났습니다. 73 중요하게도, 지방산 산화(FAO)와 관련된 유전적 특징은 MYC 고발현 TNBC의 공격성과 불량한 임상 결과에 기여하며, 이는 이러한 종양의 필수적인 생체 에너지 대사 경로임을 시사합니다.73 실제로, 에토모시르로 CPT1을 억제하고 이에 따라 FAO를 억제하면 MYC 고발현 TNBC나 RPBC의 원발 종양 성장 속도가 유의미하게 감소하지만, MYC 저발현 TNBC나 RPBC에서는 그렇지 않습니다. 73 TNBC의 β-산화에 대한 대사 의존성을 활용하는 가능성은 전이성 질환 치료에서도 입증되었으며, CUB 도메인 함유 단백질 1(CDCP1) 억제는 TNBC가 이동 및 전이 과정에서 LD에 저장된 지방산을 산화하는 능력을 크게 저해합니다. 67 전반적으로, 암 세포의 일반적인 특징으로 지질 균형 장애를 고려하는 것보다, 이러한 변화의 분자적 하위 유형, 조직 및 전체 종양 미세환경 맥락을 이해하는 것이 중요합니다. 이는无疑히 지질 대사 관련 특정 경로를 차단하는 대사 억제제의 더 나은 분류 방법과 표적 적용으로 이어질 것입니다.

Regulation of lipid metabolism by oncogenic signalling

Oncogenic signalling pathways can directly regulate metabolic enzymes involved in lipid metabolism, and are therefore integral in shaping the tumour lipidome. The most frequently dysregulated signalling pathway in human cancers is PI3K–AKT signalling, which can be activated through the stimulation of growth-factor receptor tyrosine kinases (RTKs) including human epidermal growth-factor receptor 2 (HER2) and the insulin receptor, or acquirement of oncogenic mutations in PIK3CA, the gene encoding the p110α catalytic subunit of class I PI3Ks.74,75,76,77 PIK3CA is, in fact, one of the most commonly mutated genes in carcinomas, with up to a third of all human cancers and 40% of breast cancers carrying gain-of-function mutations.78 There have been several extensive reviews on the specific nodes that constitute PI3K signalling,74,75,79 and their oncogenic consequences in terms of promoting growth, proliferation and survival, hence these concepts are only briefly introduced here.

HER2-amplified breast cancers are closely associated with hyperactivation of PI3K signalling, with more than 80% of tumours displaying increased phosphorylation of AKT on Ser473 and Thr308.80 Furthermore, an important feature of HER2-positive tumours that contributes to their aggressiveness is sustained upregulation of de novo lipogenesis.81 Indeed, overexpression‎ of HER2 in non-transformed epithelial cells induces a lipogenic phenotype dependent on FASN activation that is reminiscent of cancer cells, whilst inhibition of HER2 or de novo lipogenesis ablates oncogenic activity and induces apoptosis.82 

This suggests that oncogenic signalling downstream of HER2 may activate several complementary pathways that converge on increased lipogenesis. Activation of AKT contributes to two essential processes for de novo lipid synthesis: the shuttling of metabolic intermediates to provide carbon sources for anabolism, and the synthesis of reducing equivalents in the form of NADPH to fuel lipogenesis.83 For instance, AKT can directly phosphorylate and activate ACLY, thus increasing acetyl-CoA synthesis.84 Moreover, NADPH is an essential cofactor for anabolic metabolism, and specifically for the condensation reaction of acetyl-CoA and malonyl-CoA catalysed by FASN.85 AKT can indirectly promote NADPH production by activating the nuclear factor-like 2 (Nrf2) transcription factor,20,86 leading to the transcription of genes involved in NADPH synthesis, including 6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1).87,88 More recently, AKT has been shown to directly contribute to the cellular pool of NADPH by acutely activating nicotinamide adenine dinucleotide kinase (NADK), resulting in increased nicotinamide adenine dinucleotide phosphate (NADP+) production.89 Mechanistically, AKT-mediated phosphorylation of NADK at Ser44, Ser46 and Ser48 within the N-terminal domain maintains NADK in an active state by preventing its autoinhibition.89 Importantly, NADK is the only enzyme in mammalian cells that converts NAD+ into NADP+, the latter of which can be reduced to NADPH to sustain de novo lipogenesis (Fig. 3).89

암 유발 신호전달 경로에 의한 지질 대사 조절

암 유발 신호전달 경로는

지질 대사 관련 대사 효소를 직접 조절할 수 있으며,

따라서 종양 지질체 구성에 중요한 역할을 합니다.

인간 암에서 가장 자주 이상 조절되는 신호전달 경로는

PI3K–AKT 신호전달 경로로,

성장 인자 수용체 티로신 키나제(RTKs)의 자극을 통해 활성화될 수 있으며,

이는 인간 상피 성장 인자 수용체 2(HER2)와 인슐린 수용체를 포함합니다.

또는 PI3K의 p110α 촉매 서브유닛을编码하는 PIK3CA 유전자에 종양 유발 돌연변이가 발생할 수 있습니다. 74,75,76,77 PIK3CA는 실제로 암종에서 가장 흔히 변이되는 유전자 중 하나로, 모든 인간 암의 최대 3분의 1과 유방암의 40%에서 기능 획득 변이를 가지고 있습니다. 78 PI3K 신호전달 경로의 특정 구성 요소와 그 발암적 영향(성장, 증식, 생존 촉진)에 대한 광범위한 리뷰가 여러 차례 발표되었으며,74,75,79 따라서 이 개념들은 여기서는 간략히 소개됩니다.

HER2 증폭 유방암은 PI3K 신호전달의 과활성화와 밀접하게 연관되어 있으며, 종양의 80% 이상에서 AKT의 Ser473 및 Thr308 잔기 인산화 증가가 관찰됩니다. 80 또한 HER2 양성 종양의 공격성에 기여하는 중요한 특징 중 하나는 지속적 신생 지방 생성의 상향 조절입니다.81 실제로, 비전환 상피 세포에서 HER2 과발현은 FASN 활성화에 의존하는 암 세포와 유사한 지방 생합성 형질을 유도하며, HER2 또는 신생 지방 생성의 억제는 종양 유발 활성을 소멸시키고 아포토시를 유도합니다.82

이는 HER2 하류의 종양 유발 신호전달이 증가된 지방 생성에 수렴하는 여러 보완적 경로를 활성화할 수 있음을 시사합니다. AKT 활성화는 신생 지방 합성에 필수적인 두 가지 과정에 기여합니다: 대사 중간체의 이동을 통해 동화 작용에 필요한 탄소 원료를 공급하는 것과 NADPH 형태의 환원 등가물을 합성하여 지방 생성을 촉진하는 것입니다.83 예를 들어, AKT는 ACLY를 직접 인산화 및 활성화하여 아세틸-CoA 합성을 증가시킵니다. 84 또한 NADPH는 동화 대사, 특히 FASN에 의해 촉매되는 아세틸-CoA와 말론일-CoA의 축합 반응에 필수적인 보조인자입니다. 85 AKT는 핵 인자 유사 2(Nrf2) 전사 인자를 활성화하여 NADPH 생산을 간접적으로 촉진하며,20,86 이는 NADPH 합성에 관여하는 유전자(6-포스포글루코네이트 탈수소효소(6PGD), 글루코스-6-포스페이트 탈수소효소(G6PD), 말산 효소 1(ME1) 등)의 전사를 유도합니다. 87,88 최근 연구에서 AKT는 니코틴아미드 아데닌 디뉴클레오티드 키나제(NADK)를 급성적으로 활성화하여 NADPH의 세포 내 풀에 직접 기여하는 것으로 밝혀졌습니다. 이는 니코틴아미드 아데닌 디뉴클레오티드 인산(NADP+) 생산 증가로 이어집니다. 89 메커니즘적으로, AKT에 의한 NADK의 N-말단 도메인 내 Ser44, Ser46 및 Ser48에서의 인산화는 NADK의 자가억제를 방지함으로써 활성 상태를 유지합니다.89 중요하게도, NADK는 포유류 세포에서 NAD+를 NADP+로 전환하는 유일한 효소이며, 후자는 NADPH로 환원되어 신규 지방 생합성을 유지합니다(그림 3).89

Fig. 3

Regulation of lipid metabolism by PI3K–mTOR signalling. PI3K signalling is the most frequently dysregulated pathway in cancer, and stimulates growth, proliferation and survival. Activation of receptor tyrosine kinases recruits PI3Kα to the plasma membrane where it phosphorylates PIP2 to PIP3. AKT binds to PIP3, allowing activation by PDK1 and mTORC2. AKT directly promotes lipogenesis by stabilising SREBP1c through inhibition of GSK3β, activation of ACLY to generate acetyl-CoA and phosphorylation of NADK to produce NADP+ for NADPH synthesis. PI3K signalling is also closely linked to mTORC1 and mTORC2. mTORC1 regulates lipogenesis through inhibition of lipin-1, which is a negative regulator of nuclear SREBP1c, and activation of the splicing factor SRPK2, thereby promoting the expression‎ of lipogenic enzymes, including ACLY, FASN and ACSS2. Finally, mTORC2 activation supports lipogenesis through AKT-dependent and -independent mechanisms, with the latter encompassing phosphorylation of SGK1 and PKCs, and subsequent activation of SREBP1c.

PI3K–mTOR 신호전달 경로를 통한 지질 대사 조절. 

PI3K 신호전달 경로는 암에서 가장 자주 이상 조절되는 경로이며, 성장, 증식 및 생존을 촉진합니다. 수용체 티로신 키나제의 활성화는 PI3Kα를 세포막으로 모집하여 PIP2를 PIP3로 인산화합니다. AKT는 PIP3에 결합하여 PDK1과 mTORC2에 의해 활성화됩니다. AKT는 GSK3β의 억제를 통해 SREBP1c를 안정화시키고, ACLY를 활성화하여 아세틸-CoA를 생성하며, NADK의 인산화를 촉진하여 NADPH 합성에 필요한 NADP+를 생산함으로써 직접적으로 지질 생성을 촉진합니다. PI3K 신호전달은 mTORC1과 mTORC2와도 밀접하게 연관되어 있습니다. mTORC1은 핵 내 SREBP1c의 음성 조절인자인 lipin-1을 억제하고 스플라이싱 인자 SRPK2를 활성화하여 ACLY, FASN 및 ACSS2와 같은 지방생성 효소의 발현을 촉진합니다. 마지막으로, mTORC2 활성화는 AKT 의존적 및 비의존적 메커니즘을 통해 지질 생합성을 지원하며, 후자는 SGK1 및 PKC의 인산화 및 이후 SREBP1c 활성화를 포함합니다. 

약어: PIP3, 인산화 인오시톨 (3,4,5)-트리인산염; PIP2, 인산화 인오시톨 (4,5)-비스인산염; mTORC, 포유류 라파마이신 표적 복합체; SREBP, 스테롤 조절 요소 결합 단백질; SGK, 혈청 및 글루코코르티코이드 유도 단백질 키나제

Abbreviations: PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol (4,5)-bisphosphate; mTORC, mammalian target of rapamycin complex; SREBP, sterol regulatory element-binding protein; SGK, serum- and glucocorticoid-induced protein kinase

1; PKC, protein kinase C; GSK3, glycogen synthase kinase; FBXW7, F-Box and WD repeat domain containing 7; ACLY, ATP–citrate lyase, PDK1, phosphoinositide-dependent kinase 1; NADK, NAD+ kinase; NAD+, nicotinamide adenine dinucleotide; NADP+, nicotinamide adenine dinucleotide phosphate; SRPK2; SR-protein-specific kinase 2; S6K1, ribosomal protein S6 kinase β-1; FASN, fatty acid synthase; ACC, acyl-CoA synthetase short-chain family member 2.

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Intimately linked with PI3K activation is signalling through the mammalian target of rapamycin (mTOR) complexes. mTOR is a serine/threonine protein kinase that is the predominant catalytic subunit of the protein complex mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).90 Both are multiprotein complexes, and are distinguished mainly through their associations of either Raptor (regulatory protein associated with mTOR) in mTORC1, or Rictor (rapamycin-insensitive companion of mTOR) in mTORC2.90 AKT is a potent activator of mTORC1 by phosphorylating and inactivating its main negative regulators tuberous sclerosis complex components 1 and 2 (TSC1/2).90 Several metabolic processes are activated by mTORC1, including oxidative phosphorylation by promoting mitochondrial biosynthesis,91 sustaining de novo nucleotide synthesis92 and lipogenesis.93 The processing of the lipogenesis transcriptional regulator SREBP1 into its mature active form is strongly influenced by PI3K–AKT–mTORC1-dependent mechanisms; hence, the expression‎ of key lipogenic enzymes, such as FASN, ACC1 and ACLY is suppressed following mTORC1 inhibition by acute rapamycin inhibition or Raptor knockdown.93,94 One of these mechanisms involves the mTORC1-dependent regulation of lipin-1.95 Interestingly, mTORC1 directly phosphorylates and inactivates lipin-1 leading to its sequestration in the cytoplasm.95 Upon mTORC1 inhibition, active lipin-1 translocates to the nucleus and induces significant nuclear reshaping, culminating in reduced SREBP-transcriptional activity (Fig. 3).95 Although not fully elucidated, this regulation may be dependent on the lipid phosphatase activity of lipin-1 that specifically acts on PAs: it is, therefore, conceivable that modulation of the lipid architecture in the nucleus and subsequent alteration of the nuclear lamina may directly affect SREBP activity.95 mTORC1 also regulates the expression‎ of lipogenic genes independently of SREBPs.96 Mechanistically, this requires the mTORC1–S6 kinase 1 (S6K1)–serine/arginine protein kinase 2 (SRPK2) activation of the U1 small nuclear ribonucleoprotein 70 kDa (U1-70K), leading to increased mRNA splicing of genes involved in de novo lipogenesis such as FASN, ACLY and ACSS2 (Fig. 3).96 Notably, inhibition of mTORC1 with Torin-1 reduces spliceosome formation, and knockdown of SRPK2 significantly attenuates mRNA stability and expression‎ of the aforementioned lipogenic enzymes, resulting in reduced tumour growth in vivo.96

It is noteworthy that several oncogenes converge on mTORC1 to promote lipogenesis. One of the most relevant in the context of tumorigenesis is activation of Ras.97 KRAS in particular is frequently mutated in colorectal and non-small-cell lung carcinomas, with the G12V missense accounting for the majority of detected mutations.97 Consequent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) activates mTORC1 through inhibition of TSC1/2, and contributes to lipidomic rewiring encompassing elevated synthesis of glycerophospholipids and FAs including palmitate, oleic acid and docosahexaenoic acid in lung cancers.94,98,99 Furthermore, KRASG12V also contributes to increased incorporation of acetate into endogenously synthesised lipids, potentially suggesting a dependence on ACSS2 to synthesise acetyl-CoA for de novo lipogenesis.94

In addition to mTORC1, hyperactivation of PI3K signalling can also induce mTORC2 activity, and although less well characterised than mTORC1, it is becoming increasingly appreciated that mTORC2 is an important mediator of metabolic reprogramming in cancer cells. mTORC2 functions as a pivotal signalling hub for driving FA metabolism, and this is mediated not only through the activation of downstream AGC kinases, including AKT, serum- and glucocorticoid-regulated kinases (SGKs) and protein kinase Cs (PKCs), but also through reciprocal stimulation of mTORC2 by AKT following phosphorylation of SIN1 on Thr86.79,100,101 In support of a broad role of mTORC2 at regulating whole-body metabolism, Rictor knockout causes insulin insensitivity characterised by reduced glucose uptake in hepatocytes and overall attenuation of insulin-stimulated de novo lipogenesis through inhibition of SREBP1c maturation.100 An important role for mTORC2 signalling in tumorigenesis has been established in hepatocellular carcinogenesis, where it drives the progression of fatty liver disease to cancer in liver-specific PTEN−/− and Tsc1−/− mouse models.102 Through activation of SREBP1c, mTORC2 induces widespread alterations in the hepatocellular lipidome culminating in de novo synthesis of sphingolipids, glycerophospholipids and cardiolipins, which increase mitochondrial respiration.102 Importantly, inhibition of mTORC2, but not mTORC1, leads to a reduction in the elevated expression‎ of de novo lipogenesis genes including FASN, and overall hepatocellular lipid content, culminating in attenuated growth of PTEN- and Tsc1-null hepatocellular carcinomas.102 These observations are particularly relevant in light of previous in vivo data suggesting that mTORC1 activation alone is insufficient to stimulate lipid synthesis without functional AKT.103

Independently of mTORC1, AKT promotes the stability of mature SREBP1c by inhibiting glycogen synthase kinase-3 (GSK3), which phosphorylates and promotes its ubiquitylation and proteasomal degradation (Fig. 3).104 In addition, by inhibiting the expression‎ of Insig2, AKT positively regulates the translocation of SREBP1c from the ER membrane to the Golgi apparatus, where it can be processed into the transcriptionally active form.103 Therefore, it is conceivable that mTORC2 activation and its downstream signalling nodes could play a more dominant role in lipid homoeostasis than previously appreciated.102

An important aspect of mTORC2 signalling is its capacity to stimulate several AKT-independent compensatory signalling axes, posing significant challenges for the successful therapeutic targeting of PI3K–mTOR signalling.105 In addition to AKT, mTORC2 can directly phosphorylate and activate several SGK and PKC isoforms that can stimulate lipogenesis (Fig. 3). For instance, in yeast models, mTORC2 promotes ceramide synthesis by activating Ypk2, the human orthologue of which is SGK1.106 Although not yet comprehensively studied in human cells, the potential regulation of ceramide synthesis by mTORC2 and SGK1 could provide a compensatory pathway for sustaining glycerophospholipid synthesis in cancer independently of canonical AKT–mTORC1 activities.106 In terms of PKC signalling, mTORC2 phosphorylates the hydrophobic motif of several isoforms, including PKCβII, PKCε and PKCζ on Ser660, Ser729 and Thr560, respectively (Fig. 3).107,108,109 The regulation of cancer cell metabolism by PKCs has been characterised in the context of lipid homoeostasis and includes the PKCβ-dependent stimulation of de novo lipogenesis by activating the transcription of SREBPF1 directly through recruitment of Sp1 to the promoter region.110 Moreover, the atypical PKCζ and PKCλ/ι isoforms have been shown to be the predominant mediators of hepatic lipogenesis downstream of insulin-induced PI3K signalling.111 The expression‎ of SREBPF1, FASN, as well as glucose uptake, cholesterol and triglyceride levels, are all reduced following deletion of Pik3r1 and Pik3r2.111 Notably, reconstituting myristoylated AKT restores hepatic glucose metabolism, whilst SREBP1c expression‎ and lipogenesis are rescued following overexpression‎ of PKCζ/λ.111 These findings indicate that PI3K signalling regulates metabolic homoeostasis in the liver through two distinct pathways: one involving AKT-dependent glucose uptake, and the second requiring PKCζ/λ to sustain lipid synthesis.111

It is well established that PI3K signalling regulates a myriad of cellular metabolic processes in cancer, but how these are integrated in the context of dysregulated FA metabolism is still obscure. The PI3K–AKT pathway is well-known to be the major signalling cascade contributing to the Warburg effect by directly facilitating glucose uptake and glycolysis through activation of GLUT1 and hexokinase.112 Furthermore, AKT has been shown to promote HIF1α mRNA translation in an mTORC1-dependent fashion even under aerobic conditions, thus contributing to uncoupling of glycolysis and mitochondrial oxidative phosphorylation through inhibition of pyruvate dehydrogenase.113 If one is to consider this metabolic rewiring in isolation, then it becomes counterintuitive as to how PI3K signalling promotes lipid metabolism, particularly when functional oxidative phosphorylation is required for citrate synthesis during lipogenesis and β-oxidation.

It is, therefore, necessary to re-examine the notion that cancer cells displaying elevated aerobic glycolysis must also have impaired oxidative phosphorylation. In the context of PI3K signalling, metabolic pathways contributing to both the synthesis of metabolic intermediates required for lipogenesis and promotion of mitochondrial bioenergetics are activated. For instance, glucose-6-phosphate generated during the first step of glycolysis can be shunted to the pentose phosphate pathway (PPP) to contribute in the production of NADPH, which plays a key role in the sustainment of anabolic processes and detoxification of ROS in rapidly proliferating cells.88,114 As discussed previously, AKT can also directly facilitate NADPH synthesis following phosphorylation and activation of NADK.89 Furthermore, mTORC1 and mTORC2 downstream of oncogenic PI3K promote oxidative phosphorylation through PGC-1α-dependent mitochondrial biosynthesis, and synthesis of cardiolipins, which enhance respiration and improve mitochondrial activity.91,102 Therefore, hyperactive PI3K signalling provides a clear metabolic advantage to cancer cells as it not only increases the synthesis of metabolic intermediates required for anabolic metabolism, but also promotes respiration to generate citrate from acetyl-CoA for de novo lipogenesis.

In general, PI3K–AKT signalling promotes lipid synthesis whilst inhibiting lipolysis and β-oxidation.115 However, the precise involvement of the PI3K pathway in balancing the oxidation of FAs and glucose is more complex. Insights have been provided by studies focussing on glucose and lipid homoeostasis in type 2 diabetes. Hyperinsulinaemia activates the insulin receptor and PI3K signalling, contributing to increased CD36 membrane translocation and uptake of exogenous FAs.116 At the onset of insulin resistance, GLUT4 expression‎ and translocation is inhibited, leading to increased blood glucose levels, decreased glycolysis and high FA β-oxidation of intracellular lipid pools.117 In terms of specific mechanisms, the accumulation of FAs in response to insulin resistance may drive DAG synthesis, which can activate conventional PKC isoforms, leading to the phosphorylation of insulin receptor substrate 1 (IRS1) and consequent inhibition of PI3K–AKT signalling.118 Moreover, dysregulated lipid signalling could induce a negative-feedback loop initiated by the activation of mTORC1–p70S6K and its subsequent phosphorylation-induced inhibition of IRS1.119,120 Given that insulin resistance and obesity are becoming increasingly associated with cancer, it is conceivable that PI3K signalling is central to this phenomenon. In this context, attenuation of PI3K signalling following obesity-induced insulin resistance may shift the metabolic balance from lipid synthesis to lipolysis and β-oxidation.115 As previously discussed in this review, increased lipolysis particularly in adipocyte-rich microenvironments generates free FAs that can be utilised by cancer cells,7,11 whilst β-oxidation contributes to ATP and NADPH synthesis.14 Thus, the effects of PI3K signalling on lipid metabolism and tumorigenesis are paradoxical: on one hand, active PI3K signalling supports tumorigenesis through enhanced de novo lipogenesis, but on the other it inhibits lipolysis and β-oxidation, both of which are key at promoting cancer cell proliferation and metastasis. In order to reconcile the seemingly disparate regulatory mechanisms linking PI3K signalling and lipid metabolism, it may be necessary to consider whole-body metabolism and obesity as factors that dictate the dependencies of tumours for specific metabolic pathways.

PI3K 활성화와 밀접하게 연관된 신호전달 경로는 포유류 라파마이신 표적 단백질(mTOR) 복합체입니다. mTOR는 세린/트레오닌 단백질 키나아제로, 단백질 복합체 mTOR 복합체 1(mTORC1)과 mTOR 복합체 2(mTORC2)의 주요 촉매 서브유닛입니다. 90 두 복합체 모두 다중 단백질 복합체이며, 주로 mTORC1에 연관된 Raptor(mTOR와 연관된 조절 단백질) 또는 mTORC2에 연관된 Rictor(라파마이신에 민감하지 않은 mTOR 동반 단백질)와의 연관성을 통해 구분됩니다.90 AKT는 mTORC1의 주요 음성 조절인자인 결절성 경화증 복합체 구성 요소 1과 2(TSC1/2)를 인산화하고 비활성화함으로써 mTORC1의 강력한 활성화제입니다. 90 mTORC1은 미토콘드리아 생합성을 촉진하여 산화적 인산화,91 신규 핵산 합성 유지,92 지방 생합성 등 여러 대사 과정을 활성화합니다. 93 지질 생합성 전사 조절인자 SREBP1의 성숙한 활성 형태로의 처리 과정은 PI3K–AKT–mTORC1 의존적 메커니즘에 의해 강하게 영향을 받습니다. 따라서 급성 라파마이신 억제나 Raptor 발현 억제에 따른 mTORC1 억제 시, FASN, ACC1 및 ACLY와 같은 주요 지질 생합성 효소의 발현이 억제됩니다. 93,94 이 중 하나는 mTORC1에 의존하는 lipin-1의 조절 메커니즘입니다.95 흥미롭게도 mTORC1은 lipin-1을 직접 인산화하고 비활성화시켜 세포질에 격리시킵니다.95 mTORC1 억제 시 활성 lipin-1은 핵으로 이동하여 핵 구조 재편성을 유발하며, 이는 SREBP 전사 활성 감소로 이어집니다(그림 3). 95 이 조절 메커니즘은 완전히 규명되지 않았지만, lipin-1의 지질 인산화 효소 활성이 PAs에 특이적으로 작용하기 때문일 수 있습니다. 따라서 핵 내 지질 구조의 조절과 핵 층의 변화가 SREBP 활성에 직접적인 영향을 미칠 수 있습니다.95 mTORC1은 SREBPs와 독립적으로 지질 합성 유전자 발현을 조절합니다. 96 메커니즘적으로 이는 mTORC1–S6 키나제 1 (S6K1)–세린/아르기닌 단백질 키나제 2 (SRPK2) 활성화로 U1 소핵 리보핵단백질 70 kDa (U1-70K)가 활성화되어 FASN, ACLY 및 ACSS2와 같은 신규 지방 생성에 관여하는 유전자의 mRNA 스플라이싱이 증가합니다 (그림 3). 96 주목할 점은 mTORC1을 Torin-1로 억제하면 스플라이소좀 형성이 감소하며, SRPK2의 발현을 억제하면 앞서 언급된 지방 생합성 효소의 mRNA 안정성과 발현이 유의미하게 감소하여 체내 종양 성장도 감소한다는 것입니다.96

mTORC1에 수렴하여 지질 생성을 촉진하는 여러 종양 유전자들이 존재합니다. 종양 발생 맥락에서 가장 관련성이 높은 것은 Ras의 활성화입니다.97 특히 KRAS는 대장암과 비소세포 폐암에서 자주 변이되며, 검출된 변이의 대부분은 G12V 미스센스 변이입니다. 97 이후 세포외 신호 조절 키나제 1/2 (ERK1/2)의 활성화는 TSC1/2 억제를 통해 mTORC1을 활성화하며, 폐암에서 글리세로포스파티드 및 팔미트산, 올레산, 도코사헥사엔산 등 지방산의 합성 증가를 포함한 지방체 재편성에 기여합니다. 94,98,99 또한 KRASG12V는 내인성 지질 합성에 아세테이트의 증가된 포함에 기여하며, 이는 ACSS2에 의존하여 아세틸-CoA를 합성하여 신규 지질 생성에 필요할 수 있음을 시사합니다.94

mTORC1 외에도 PI3K 신호전달의 과활성화는 mTORC2 활성을 유도할 수 있으며, mTORC1보다 덜 잘 연구되었지만, mTORC2가 암 세포의 대사 재프로그래밍에 중요한 매개체로 점점 더 인정받고 있습니다. mTORC2는 지방산 대사 촉진에 핵심적인 신호 전달 허브로 기능하며, 이는 하류 AGC 키나제(AKT, 혈청 및 글루코코르티코이드 조절 키나제(SGKs), 단백질 키나제 C(PKCs))의 활성화뿐만 아니라 SIN1의 Thr86 인산화 후 AKT에 의한 mTORC2의 상호 자극을 통해 매개됩니다. 79,100,101 mTORC2가 전신 대사 조절에 광범위한 역할을 한다는 것을 뒷받침하는 연구에서, Rictor 결손은 간세포에서의 포도당 흡수 감소와 SREBP1c 성숙 억제를 통해 인슐린 자극에 의한 신규 지방 생성의 전반적인 억제를 특징으로 하는 인슐린 저항성을 유발합니다. 100 mTORC2 신호전달의 종양 발생에서의 중요성은 간세포 암 발생에서 확립되었으며, 간 특이적 PTEN−/− 및 Tsc1−/− 마우스 모델에서 지방간 질환에서 암으로의 진행을 촉진합니다. 102 SREBP1c 활성화를 통해 mTORC2는 간세포 지질체에 광범위한 변화를 유도하여 스핑고지질, 글리세로포스포지질 및 카르디올리핀의 신규 합성을 촉진하며, 이는 미토콘드리아 호흡을 증가시킵니다. 102 중요하게도, mTORC2 억제는 mTORC1 억제와 달리 FASN을 포함한 신규 지방 생합성 유전자 발현 증가와 전체 간세포 지방 함량을 감소시켜 PTEN- 및 Tsc1- 결핍 간세포 암종의 성장 억제를 초래합니다. 102 이러한 관찰 결과는 이전 in vivo 데이터에서 AKT 기능이 결여된 상태에서 mTORC1 활성화만으로는 지질 합성을 자극하기에 충분하지 않다는 점을 고려할 때 특히 중요합니다.103

mTORC1과 독립적으로, AKT는 글리코겐 합성 키나제-3 (GSK3)를 억제함으로써 성숙한 SREBP1c의 안정성을 촉진합니다. GSK3는 SREBP1c를 인산화하고 그 유비퀴틴화 및 프로테아좀 분해를 촉진합니다 (그림 3). 104 또한 AKT는 Insig2의 발현을 억제함으로써 SREBP1c가 ER 막에서 골지체로 이동하는 것을 긍정적으로 조절합니다. 여기서 SREBP1c는 전사 활성 형태로 처리됩니다.103 따라서 mTORC2 활성화와 그 하류 신호 전달 노드가 이전에 인식된 것보다 지방 균형 유지에 더 중요한 역할을 할 수 있다는 것이 추론됩니다.102

mTORC2 신호전달의 중요한 측면은 AKT 독립적 보상 신호축을 자극하는 능력으로, PI3K–mTOR 신호전달의 성공적인 치료적 표적화에 심각한 도전 과제를 제기합니다.105 AKT 외에도 mTORC2는 지질 생성을 자극할 수 있는 여러 SGK 및 PKC 이소형을 직접 인산화하고 활성화합니다(그림 3). 예를 들어, 효모 모델에서 mTORC2는 인간 동형체인 SGK1의 효소인 Ypk2를 활성화하여 세라마이드 합성을 촉진합니다.106 인간 세포에서 아직 완전히 연구되지 않았지만, mTORC2와 SGK1에 의한 세라마이드 합성 조절은 AKT–mTORC1 신호전달 경로에 독립적으로 암에서 글리세로포스파티드 합성을 유지하는 보상 경로를 제공할 수 있습니다. 106 PKC 신호전달 측면에서 mTORC2는 PKCβII, PKCε 및 PKCζ의 여러 이소형에서 각각 Ser660, Ser729 및 Thr560 위치의 친수성 모티프를 인산화합니다(그림 3). 107,108,109 PKC에 의한 암 세포 대사 조절은 지질 균형 조절 맥락에서 특징지어졌으며, PKCβ에 의존적인 SREBPF1 전사 활성화로 Sp1을 프로모터 영역에 모집하여 신규 지질 생성을 자극하는 것을 포함합니다. 110 또한, 비전형적 PKCζ 및 PKCλ/ι 이소형은 인슐린 유도 PI3K 신호전달 하류에서 간 지방생성의 주요 매개체로 확인되었습니다.111 Pik3r1 및 Pik3r2 삭제 시 SREBPF1, FASN 발현 및 포도당 흡수, 콜레스테롤 및 트리글리세라이드 수치가 모두 감소합니다. 111 특히, 마이리스토일화된 AKT를 재구성하면 간 포도당 대사 기능이 회복되며, PKCζ/λ 과발현 시 SREBP1c 발현과 지방 생성이 회복됩니다.111 이러한 결과는 PI3K 신호전달이 간 대사 균형을 두 가지 서로 다른 경로를 통해 조절한다는 것을 보여줍니다: 하나는 AKT 의존적 포도당 흡수 경로이며, 다른 하나는 PKCζ/λ를 통해 지방 합성을 유지하는 경로입니다.111

PI3K 신호전달이 암에서 다양한 세포 대사 과정을 조절한다는 것은 잘 알려져 있지만, 이들이 지방산 대사 장애 맥락에서 어떻게 통합되는지는 여전히 불분명합니다. PI3K–AKT 경로는 GLUT1과 헥소키나제의 활성화를 통해 포도당 섭취와 글리코겐 분해를 직접 촉진함으로써 워버그 효과에 기여하는 주요 신호 전달 경로로 잘 알려져 있습니다.112 또한 AKT는 mTORC1에 의존적으로 HIF1α mRNA 번역을 촉진하여 산소 존재 하에서도 피루vate dehydrogenase 억제를 통해 글리코겐 분해와 미토콘드리아 산화 인산화 사이의 분리(uncoupling)에 기여합니다. 113 이 대사 재편을 단독으로 고려할 경우, PI3K 신호전달이 특히 지질 생합성 과정에서 시트르산 합성에 필요한 기능적 산화 인산화가 요구되는 상황에서 지질 대사를 촉진하는 메커니즘이 직관적이지 않습니다.

따라서, 유산소 당분해가 증가한 암 세포가 반드시 산화 인산화 장애를 동반해야 한다는 개념을 재검토할 필요가 있습니다. PI3K 신호전달 맥락에서, 지질 생성에 필요한 대사 중간체 합성과 미토콘드리아 생체에너지 대사를 촉진하는 대사 경로가 활성화됩니다. 예를 들어, 글리코겐 분해의 첫 단계에서 생성된 글루코스-6-인산은 펜토스 인산 경로(PPP)로 분기되어 NADPH 생성에 기여합니다. NADPH는 빠르게 증식하는 세포에서 아나볼릭 과정의 유지와 활성산소종(ROS) 해독에 핵심 역할을 합니다. 88,114 앞서 논의된 바와 같이, AKT는 NADK의 인산화 및 활성화 후 NADPH 합성을 직접 촉진합니다.89 또한, 발암성 PI3K 하류의 mTORC1 및 mTORC2는 PGC-1α 의존적 미토콘드리아 생합성을 통해 산화적 인산화 및 카르디올리핀 합성을 촉진하여 호흡을 강화하고 미토콘드리아 활성을 개선합니다. 91,102 따라서 과활성 PI3K 신호전달은 암 세포에 명확한 대사적 이점을 제공합니다. 이는 대사 중간체 합성을 증가시켜 동화 대사 요구를 충족시킬 뿐만 아니라 아세틸-CoA로부터 시트르산을 생성하여 신규 지방 생합성을 촉진하기 때문입니다.

일반적으로 PI3K–AKT 신호전달은 지질 합성을 촉진하며, 지질 분해와 β-산화를 억제합니다.115 그러나 PI3K 경로가 지방산(FAs)과 포도당의 산화 균형을 조절하는 정확한 메커니즘은 더 복잡합니다. 제2형 당뇨병에서의 포도당 및 지질 균형에 초점을 맞춘 연구들이 이에 대한 통찰을 제공했습니다. 고인슐린혈증은 인슐린 수용체를 활성화하고 PI3K 신호전달을 촉진하여 외인성 지방산의 CD36 막 이동 및 흡수를 증가시킵니다.116 인슐린 저항성이 발생하면 GLUT4 발현 및 이동이 억제되어 혈당 수치가 상승하고 글리코lysis가 감소하며 세포 내 지방 풀의 지방산 β-산화가 증가합니다. 117 구체적인 메커니즘 측면에서, 인슐린 저항성에 대한 반응으로 지방산의 축적은 DAG 합성을 촉진할 수 있으며, 이는 전통적인 PKC 이소형을 활성화시켜 인슐린 수용체 서브스트레이트 1(IRS1)의 인산화를 유발하고 PI3K–AKT 신호전달 경로의 억제를 초래합니다. 118 또한, 지질 신호전달의 이상은 mTORC1–p70S6K 활성화에 의해 시작되는 음의 피드백 루프를 유발할 수 있으며, 이는 IRS1의 인산화 유도 억제를 초래합니다.119,120 인슐린 저항성과 비만이 암과 점점 더 연관되고 있다는 점을 고려할 때, PI3K 신호전달이 이 현상의 중심에 있을 가능성이 있습니다. 이 맥락에서 비만 유발 인슐린 저항성에 따른 PI3K 신호전달의 억제는 대사 균형을 지질 합성에서 지질 분해 및 β-산화로 전환시킬 수 있습니다.115 이 리뷰에서 이전에 논의된 바와 같이, 특히 지방세포가 풍부한 미세환경에서 증가한 지질 분해는 암 세포에 의해 활용될 수 있는 자유 지방산을 생성하며,7,11 β-산화는 ATP 및 NADPH 합성에 기여합니다. 14 따라서 PI3K 신호전달이 지질 대사 및 종양 발생에 미치는 영향은 모순적입니다: 한쪽에서는 활성 PI3K 신호전달이 신생 지질 합성을 통해 종양 발생을 촉진하지만, 다른 쪽에서는 지질 분해와 β-산화를 억제하며, 이 두 과정은 모두 암 세포 증식 및 전이에 핵심적 역할을 합니다. PI3K 신호전달과 지질 대사 사이의 서로 다른 조절 메커니즘을 조화시키기 위해서는, 종양이 특정 대사 경로에 대한 의존성을 결정하는 요인으로 전신 대사 및 비만을 고려해야 할 수 있습니다.

Regulation of oncogenic signalling by fatty acid metabolism

Thus far, rewiring of the tumour lipidome has been largely discussed as a consequence of hyperactive oncogenic signalling and genetic aberrations. However, it is also important to acknowledge that overexpression‎ of several lipogenic enzymes occurs relatively early in tumorigenesis, and can be observed in both hyperplastic and preinvasive lesions.65,121 Therefore, it is conceivable that upregulation of de novo lipogenesis and the enzymatic network that regulates it may also dynamically and reciprocally potentiate oncogenic signalling throughout malignant transformation, rather than representing a secondary phenomenon. In support of this, mechanisms linking the bidirectional crosstalk between FASN and oestrogen receptor α (ERα) signalling have been elucidated in hormone-dependent breast cancers. In these models, both genetic and pharmacological inhibition of FASN hypersensitises ERα to oestrogen-dependent transactivation, thus leading to a synergistic induction of both oestrogen receptor element (ERE) transcriptional activity and mitogen-activated protein kinase (MAPK)–ERK signalling.122 Surprisingly, oestrogen stimulation following FASN inhibition has significant cytotoxic and cytostatic effects, despite activation of the seemingly pro-tumorigenic aforementioned processes.122 Whilst this may seem paradoxical at first, these findings highlight a novel role for FASN in modulating the thresholds required for triggering hormone receptor signalling, and consequently regulating the balance between the opposing pro-tumorigenic and anti-proliferative effects of ERα stimulation. For instance, although oestrogen signalling contributes to the upregulation of genes involved in proliferation, invasion and metastasis – such as Twist and matrix metalloproteinases 2/9 (MMP2/9) – FASN blockade leads to the nuclear accumulation of the oestradiol (E2) targets p21WAF/CIP1 and p27Kip1, culminating in cell-cycle inhibition and induction of cytostatic and cytotoxic effects in response to E2 exposure.122,123 Moreover, it is interesting to note that while E2 hyperactivates MAPK–ERK signalling following FASN inhibition, PI3K–AKT activity is attenuated.122 Indeed, there exists significant crosstalk between MAPK–ERK and PI3K–AKT signalling encompassing both positive- and negative-feedback loops, and this may explain at least one of the mechanisms responsible for the observed effects of FASN blockade and E2 exposure.124 In terms of cross-inhibition, ERK has been shown to phosphorylate the scaffold protein GRB2-associated-binding protein 1 (GAB1), thus compromising the recruitment of PI3K to the plasma membrane and downstream activation of AKT.125 Therefore, in addition to its role in de novo lipogenesis, FASN is also at the nexus of pathway integration between MAPK–ERK and PI3K–AKT pathways, and their interaction with E2–ERα signalling.122

Molecular connections have also been made between FASN and HER2 overexpression‎.121 These have largely been described at the transcriptional level, with inhibition of FASN leading to upregulation of the ets-DNA-binding protein PEA3 – a negative regulator of HER2 gene transcription – and consequent reduction in HER2 mRNA expression‎.82,126 An additional layer of regulation involves the cellular localisation of HER2 in response to FASN levels and activity. Notably, small-interfering RNA (siRNA)-mediated silencing of FASN expression‎ or chemical inhibition by using C75 markedly attenuates the membrane accumulation of HER2 and is also associated with broader alterations in cell morphology.82 Given that FASN is predominantly involved in the synthesis of saturated FAs, and these, in turn, modulate cell membrane dynamics including fluidity and lipid raft formation, inhibiting this lipogenic enzyme not only impairs the appropriate localisation of HER2 to the plasma membrane, but also impinges on the dimerisation of HER2 with epidermal growth-factor receptor (EGFR) that drives resistance to lapatinib and trastuzumab.82,127 Indeed, dual treatment with cerulenin and trastuzumab synergistically increases apoptosis in HER2-amplified breast cancer cells, indicating that FASN inhibition, and its associated effects on HER2 expression‎ and localisation, could be an attractive combinatorial therapeutic target in this breast cancer subtype.82 Furthermore, as HER2-amplified tumours are particularly dependent on PI3K signalling, FASN could play a central role in modulating the initiation of growth-factor-dependent oncogenic signalling that is required for malignancy.128,129,130,131,132

지방산 대사による 종양 유발 신호전달의 조절

현재까지 종양 지질체의 재편은 주로 과활성 종양 유발 신호전달과 유전적 이상에 따른 결과로 논의되어 왔습니다. 그러나 종양 발생 초기 단계에서 여러 지질 합성 효소의 과발현이 상대적으로 조기에 발생하며, 과증식성 및 전침습성 병변에서 관찰된다는 점을 인정하는 것도 중요합니다.65,121 따라서, 신규 지질 합성의 활성화와 이를 조절하는 효소 네트워크의 상향 조절이 악성 변환 과정에서 종양 유발 신호전달을 동적으로 상호 강화할 수 있다는 가설이 제기됩니다. 이는 단순히 이차적 현상이 아닌, 종양 발생의 초기 단계에서부터 관여하는 메커니즘일 수 있습니다. 이를 뒷받침하는 증거로, 호르몬 의존성 유방암에서 FASN과 에스트로겐 수용체 α(ERα) 신호전달 간의 양방향 교차작용을 연결하는 메커니즘이 규명되었습니다. 이러한 모델에서 FASN의 유전적 또는 약리학적 억제는 ERα의 에스트로겐 의존성 전사 활성화를 과민화시켜, 에스트로겐 수용체 요소(ERE) 전사 활성과 미토겐 활성화 단백질 키나제(MAPK)–ERK 신호전달의 시너지적 유도 를 초래합니다. 122 놀랍게도, FASN 억제 후 에스트로겐 자극은 앞서 언급된 종양 촉진 과정의 활성화에도 불구하고 유의미한 세포독성 및 세포증식 억제 효과를 나타냅니다.122 이는 처음에는 모순적으로 보일 수 있지만, 이러한 결과는 FASN이 호르몬 수용체 신호전달을 유발하는 임계값을 조절함으로써 ERα 자극의 반대되는 종양 촉진 및 항증식 효과 사이의 균형을 조절하는 새로운 역할을 강조합니다. 예를 들어, 에스트로겐 신호전달은 증식, 침습, 전이에 관여하는 유전자(예: Twist 및 매트릭스 메탈로프로테아제 2/9 (MMP2/9))의 발현을 증가시키지만, FASN 차단 시 에스트라디올 (E2)의 표적인 p21WAF/CIP1 및 p27Kip1의 핵 내 축적이 발생하여 E2 노출에 대한 세포 주기 억제 및 세포 성장 억제 및 세포 독성 효과를 유발합니다. 122,123 또한 흥미롭게도, FASN 억제 후 E2는 MAPK–ERK 신호전달을 과활성화하지만 PI3K–AKT 활성은 억제됩니다. 122 실제로 MAPK–ERK와 PI3K–AKT 신호전달 경로 사이에는 양의 및 음의 피드백 루프를 포함하는 상당한 교차작용이 존재하며, 이는 FASN 차단과 E2 노출로 인한 관찰된 효과의 메커니즘 중 하나를 설명할 수 있습니다. 124 교차 억제 측면에서, ERK는 스캐폴드 단백질 GRB2-associated-binding protein 1 (GAB1)을 인산화하여 PI3K의 세포막 결합을 방해하고 하류 AKT 활성화를 저해하는 것으로 밝혀졌습니다. 125 따라서 FASN은 신규 지방 생합성에서의 역할 외에도 MAPK–ERK 및 PI3K–AKT 경로의 경로 통합 중심에 위치하며, 이 경로들과 E2–ERα 신호전달 경로의 상호작용에도 관여합니다.122

FASN과 HER2 과발현 사이의 분자적 연결도 보고되었습니다.121 이러한 연결은 주로 전사 수준에서 설명되었으며, FASN 억제는 HER2 유전자 전사의 음성 조절자인 ets-DNA 결합 단백질 PEA3의 발현 증가를 유발하며, 이는 HER2 mRNA 발현 감소로 이어집니다.82,126 추가적인 조절 메커니즘은 FASN 수준과 활성에 따른 HER2의 세포 내 국소화에 관여합니다. 특히, 소형 간섭 RNA(siRNA)를 통한 FASN 발현 억제나 C75를 사용한 화학적 억제는 HER2의 세포막 축적을 현저히 감소시키며, 세포 형태의 광범위한 변화와도 연관되어 있습니다. 82 FASN은 주로 포화 지방산(SFA)의 합성에 관여하며, 이는 세포막 동역학(유동성 및 지질 랠트 형성)을 조절합니다. 따라서 이 지질 합성 효소의 억제는 HER2의 세포막 적정 국소화를 방해할 뿐만 아니라, 라파티닙과 트라스투주맙에 대한 저항성을 유발하는 HER2와 상피 성장 인자 수용체(EGFR)의 이량체화를 방해합니다. 82,127 실제로, 세룰레닌과 트라스투주맙의 병용 치료는 HER2 증폭 유방암 세포에서 세포 사멸을 시너지적으로 증가시키며, 이는 FASN 억제와 그에 따른 HER2 발현 및 국소화 조절이 이 유방암 하위 유형에서 유망한 병용 치료 표적이 될 수 있음을 시사합니다. 82 또한 HER2 증폭 종양은 PI3K 신호전달에 특히 의존적이며, FASN은 악성 종양 발생에 필요한 성장 인자 의존성 종양 유발 신호전달의 초기화를 조절하는 데 중심적인 역할을 할 수 있습니다.128,129,130,131,132

일반적으로 PI3K–AKT 신호전달은 지질 합성을 촉진하며, 지질 분해와 β-산화를 억제합니다.115 그러나 PI3K 경로가 지방산(FAs)과 포도당의 산화 균형을 조절하는 정확한 메커니즘은 더 복잡합니다. 제2형 당뇨병에서의 포도당 및 지질 균형에 초점을 맞춘 연구들이 이에 대한 통찰을 제공했습니다. 고인슐린혈증은 인슐린 수용체를 활성화하고 PI3K 신호전달을 촉진하여 외인성 지방산의 CD36 막 이동 및 흡수를 증가시킵니다.116 인슐린 저항성이 발생하면 GLUT4 발현 및 이동이 억제되어 혈당 수치가 상승하고 글리코lysis가 감소하며 세포 내 지방 풀의 지방산 β-산화가 증가합니다. 117 구체적인 메커니즘 측면에서, 인슐린 저항성에 대한 반응으로 지방산의 축적은 DAG 합성을 촉진할 수 있으며, 이는 전통적인 PKC 이소형을 활성화시켜 인슐린 수용체 서브스트레이트 1(IRS1)의 인산화를 유발하고 PI3K–AKT 신호전달 경로의 억제를 초래합니다. 118 또한, 지질 신호전달의 이상은 mTORC1–p70S6K 활성화에 의해 시작되는 음의 피드백 루프를 유발할 수 있으며, 이는 IRS1의 인산화 유도 억제를 초래합니다.119,120 인슐린 저항성과 비만이 암과 점점 더 연관되고 있다는 점을 고려할 때, PI3K 신호전달이 이 현상의 중심에 있을 가능성이 있습니다. 이 맥락에서 비만 유발 인슐린 저항성에 따른 PI3K 신호전달의 억제는 대사 균형을 지질 합성에서 지질 분해 및 β-산화로 전환시킬 수 있습니다.115 이 리뷰에서 이전에 논의된 바와 같이, 특히 지방세포가 풍부한 미세환경에서 증가한 지질 분해는 암 세포에 의해 활용될 수 있는 자유 지방산을 생성하며,7,11 β-산화는 ATP 및 NADPH 합성에 기여합니다. 14 따라서 PI3K 신호전달이 지질 대사 및 종양 발생에 미치는 영향은 모순적입니다: 한쪽에서는 활성 PI3K 신호전달이 신생 지질 합성을 통해 종양 발생을 촉진하지만, 다른 쪽에서는 지질 분해와 β-산화를 억제하며, 이 두 과정은 모두 암 세포 증식 및 전이에 핵심적 역할을 합니다. PI3K 신호전달과 지질 대사 사이의 서로 다른 조절 메커니즘을 조화시키기 위해서는, 종양이 특정 대사 경로에 대한 의존성을 결정하는 요인으로 전신 대사 및 비만을 고려해야 할 수 있습니다.

Metabolic regulation of the cancer epigenome

In addition to the modulation of pro-tumorigenic signalling networks, there is accumulating experimental evidence that FA metabolism exerts profound effects on the cancer epigenome, and this, in turn, regulates gene expression‎ and cellular differentiation.133 A central role for ACLY and ACSS2 has been defined in this context as these enzymes are the major sources of acetyl-CoA, which is an essential cofactor for several histone-modifying enzymes.134,135 Activation of ACLY following phosphorylation on Ser455 by AKT directly promotes acetyl-CoA synthesis and increases global histone acetylation levels, even when nutrient availability is limiting.136 Under metabolically stressful conditions such as hypoxia, ACSS2 is also involved in the nuclear recycling of acetate to acetyl-CoA, and this, in turn, promotes acetylation of histones to increase the transcription of lysosomal and autophagy-related genes, which are essential for maintaining energy homoeostasis in cancer cells.137 Importantly, the sustained synthesis of acetyl-CoA by ACLY and ACSS2 maintains a histone acetylation profile that promotes the transcription of pro-proliferative and growth genes even under nutrient-deplete conditions, thus allowing cancer cells to more rapidly induce these tumorigenic genetic programmes when microenvironmental conditions become favourable.134

The availability of acetyl-CoA also regulates cell differentiation and stemness. This is particularly relevant in cancer, as the presence of a stem-cell niche is thought to contribute to the limitless replicative potential of a tumour, as well as restoring growth of lesions that arise from therapy relapse.138 In haematological malignancies, for instance, acetyl-CoA is an obligate cofactor for CREB-binding protein (CBP)/p300, which activates the transcription factor c-Myb and induces the expression‎ of the self-renewal genes Oct4, Sox2, Klf4 and CSF1R.139 The regulation of acetyl-CoA metabolic pathways also contributes to disease progression in pancreatic ductal adenocarcinoma (PDA), with oncogenic KRAS mutations co-operating with ACLY and ACSS2 activity to promote proliferation and metastasis.140 Acetyl-CoA-induced epigenetic remodelling in PDA creates a histone profile reminiscent of the foregut endoderm in the developing embryo, and is characterised by a transcriptional programme consisting of upregulation of pro-survival and metastatic genes, including FOXA1, GATA5 and Sox2.141 Interestingly, metabolic crosstalk between ACLY–ACSS2 and the meval‎onate pathway has also been observed in PDA, with acetyl-CoA serving as the predominant substrate for cholesterol and steroid synthesis.140 The metabolic products of the meval‎onate pathway have well-characterised roles not only in the post-translational modification of oncogenes, including the farnesylation of Ras, but also on the epigenetic landscape through regulation of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs).142 Importantly, inhibition of the meval‎onate pathway with statins facilitates widespread effects on microRNA (miRNA) expression‎, reduced transcription of genes involved in folate metabolism such as dihydrofolate reductase (DHFR) as well as attenuation of HDAC activity leading to CDKN1A promoter acetylation and transcription of the tumour suppressor p21.142

Overall, the activation of lipogenic enzymes such as FASN, ACLY and ACSS2 are not just secondary events arising from hyperactive oncogenic signalling, but rather exist in a complex network involving reciprocal regulation. Furthermore, many of these enzymes generate metabolic by-products that exert profound effects on gene expression‎ and whole-cell physiology, and their functions must, therefore, be considered in this broad context.

Fatty acids support tumorigenesis and cancer progression

It is widely appreciated that FAs are essential to cancer cells because they sustain membrane biosynthesis during rapid proliferation, and provide an important energy source during conditions of metabolic stress. However, more intricate oncogenic roles of FAs and their by-products are beginning to be uncovered. These predominantly focus on the latter acting as signalling molecules that can directly regulate cellular homoeostasis, by modulating the surrounding microenvironment to create conditions that are conducive for tumour progression. The complex interplay of these multifaceted and diverse biological functions is discussed below.

Membrane structure and fluidity

FAs are essential building blocks for maintaining the structure and fluidity of the cell membrane. One of the advantages of the elevated rate of de novo lipogenesis in cancer cells is the synthesis of saturated and monounsaturated FAs, which are inherently more stable than polyunsaturated FAs because they contain fewer double bonds that can be targeted for peroxidation (Fig. 4a).143 Cancer cells with a higher degree of membrane saturation are less susceptible to oxidative stress induced by chemotherapeutic agents such as doxorubicin, whilst combinatorial inhibition of de novo lipid synthesis, either through siRNA knockdown of lipogenic enzymes or treatment with soraphen (an ACC inhibitor), synergistically increases cytotoxicity.143

Fig. 4

Fatty acids (FAs) regulate membrane architecture and oncogenic signalling pathways. a Membrane fluidity is largely determined by cholesterol levels and degree of FA desaturation. Cancer cells displaying elevated de novo lipogenesis can synthesise saturated phospholipids, which not only increases membrane rigidity, but also protects against peroxidation induced by reactive oxygen species. Conversely, highly migratory cells display more fluid membranes as a result of increased desaturation and cholesterol abundance, thus contributing to the epithelial-to-mesenchymal transition and metastasis. b FAs and their synthetic products also function as secondary messengers in signalling pathways, with the best characterised being the phosphoinositides. PI(3,4,5)P3 activates oncogenic AKT, and contributes to hyperactivation of mTORC1 and mTORC2. In addition, PI(3)P stimulates SGK3 that promotes tumorigenesis independently of AKT. Finally, phosphatidic acid can also directly bind to and activate the mTOR complexes.

Abbreviations: PI3Kα, phosphoinositide 3-kinase α; PI(4,5)P2, phosphatidylinositol (4,5)-bisphosphate; PI(3,4,5)P3, phosphatidylinositol (3,4,5)-trisphosphate; PI(3,4)P2, phosphatidylinositol (3,4)-bisphosphate; PI(3)P, phosphatidylinositol 3-phosphate; mTORC, mammalian target of rapamycin complex; PA, phosphatidic acid; PTEN, phosphatase and tensin homologue; SGK3, serum- and glucocorticoid-induced protein kinase-3; INPP4B, inositol polyphosphate-4-phosphatase type II B.

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Intracellular levels of cholesterol can also dramatically modulate membrane architecture that impacts cell migration and ultimately metastatic dissemination. Interestingly, incorporation of cholesterol in membranes generally reduces fluidity and consequently inhibits metastasis by limiting the capacity for a cell to change its shape, a process that is essential during the epithelial-to-mesenchymal transition (EMT) and intra-/extravasation from blood vessels (Fig. 4a).144 In support of this, cells undergoing EMT display increased cholesterol efflux through upregulation of the ATP-binding cassette transporter ABCA1, whilst human tumours overexpressing ABCA1 have strikingly higher rates of distant metastases.144 It is important to note, however, that increasing membrane rigidity can also be advantageous for cancer cells. This is particularly relevant for the development of multi-drug-resistant tumours, which typically contain lower levels of endogenously synthesised cholesterol and are consequently less permeable to anticancer agents.145

Epidemiological studies have highlighted controversial roles for aberrant cholesterol metabolism in cancer, thus raising important considerations for how tumours actually utilise cholesterol, and how it may be therapeutically exploited.146 For instance, elevated serum cholesterol levels are associated with increased incidence and recurrence of prostate cancer, whilst inhibition of its biosynthesis by using statins reduces colorectal, breast and endometrial cancer mortality.147,148,149 Conversely, numerous studies have shown either no association between cholesterol and cancer, or potential carcinogenic effects of statins.150,151 Therefore, resolving these disparate clinical outcomes remains a significant challenge and source of uncertainty for pursuing therapies targeting cholesterol metabolism. Perhaps insights can be gained from preclinical studies that consistently demonstrate a role for cholesterol in tumorigenesis, but in specific contexts. As discussed previously, during metastatic dissemination, cancer cells actively efflux cholesterol to maintain low membrane concentrations, thus promoting plasma membrane fluidity and EMT.144 In the case of advanced-stage disease, low cholesterol levels may, therefore, be advantageous for metastatic cells and contribute to cancer progression. On the other hand, the establishment of primary tumours are highly dependent on pro-proliferative and growth-stimulatory signalling pathways, and increased membrane cholesterol concentrations promote this through the formation of lipid rafts.152 Indeed, cholesterol-rich lipid rafts facilitate the accumulation of receptor tyrosine kinases, such as HER2 and IGF-1, to rapidly induce oncogenic signalling including PI3K–AKT.153 In this context, inhibiting cholesterol biosynthesis may be beneficial. Overall, in order to successfully exploit cholesterol metabolism as a therapeutic target in cancer, it may be necessary to first consider how the dependency of cancer cells on cholesterol changes with disease progression. With this in mind, actively lowering cholesterol in an advanced disease-stage setting may have limited or adverse effects as carcinoma cells present in metastases require low levels for EMT.144 Conversely, blocking cholesterol synthesis with statins could be more effective at inhibiting cancer initiation and proliferation at early disease stages when these tumours are more dependent on cholesterol for sustaining growth-factor-induced signalling.153

Pro-tumorigenic signalling molecules

FAs are used for the synthesis of bioactive lipids that support cellular proliferation and survival by functioning as secondary messengers in signal transduction pathways. PtdIns are among the best-characterised signalling lipids, and are composed of two FA chains connected to an inositol ring and a glycerol backbone.74 The hydroxyl groups of the inositol ring can be phosphorylated at positions 3, 4 and 5 to generate several phosphoinositide species including monophosphorylated PI(3)P, PI(4)P and PI(5)P, diphosphorylated PI(3,4)P2, PI(3,5)P2 and PI(4,5)P2 and finally triphosphorylated PI(3–5)P3 (also known as PIP3).74 Of these, PIP3 is the most extensively studied because it facilitates the localisation of AKT to the plasma membrane, leading to its subsequent activation by phosphoinositide-dependent kinase 1 (PDK1) and mTORC2 downstream of hyperactive PI3K signalling (Fig. 4b). The multifaceted roles of AKT in oncogenesis have been alluded to earlier in this review: from a metabolic viewpoint, AKT stimulates glucose uptake by stabilising GLUT1/4, and triggers de novo lipogenesis and anabolic metabolism through mTORC1-dependent and -independent mechanisms.62,84,89 Moreover, AKT promotes survival by phosphorylating and inhibiting several pro-apoptotic proteins including BAD, procaspase-9 and the FOXO transcription factors, which positively regulate the expression‎ of apoptotic enzymes.154 The regulation of oncogenic signalling by phosphoinositides can also be mediated through the activity of lipid phosphatases such as PTEN and inositol polyphosphate-4-phosphatase type II (INPP4B). PTEN in particular has been the subject of extensive study, as it acts as the main negative regulator of PI3K signalling by dephosphorylating PIP3 to PIP2.74 Conversely, other phosphatases involved in phosphoinositide metabolism can activate PI3K signalling independently of AKT. For instance, the sequential conversion of PIP3 into PI(3,4)P2 and PI(3)P by Src homology 2-containing inositol 5-phosphatase (SHIP) and INPP4B, respectively, activates SGK3 (Fig. 4b).155,156,157 PI3K–SGK3 signalling initiated by PI(3)P and INPP4B drives cell proliferation, invasion and tumour growth, demonstrating that phosphoinositides functioning as secondary messengers can dynamically regulate the initiation of different signalling axes, thus providing compensatory pro-tumorigenic effects.155,156

Since PtdIns are the precursors of phosphoinositides, their spatial and temporal regulation are essential in regulating several cellular processes. Consequently, features associated with normal FA metabolism including localisation and transport of PtdIns, as well as their enzymatic conversion into various phosphoinositide species, are often exploited by cancer cells to fuel pro-proliferative signalling. In terms of co-ordinating the spatial localisation of PtdIns pools – and by extension their downstream conversion into phosphoinositide secondary messengers – PtdIns transfer proteins (PITPs) function as central regulators.158 An important feature of PITPs is their capacity to transfer PtdIns between subcellular compartments in an ATP-independent fashion, thereby efficiently localising PtdIns that are initially synthesised in the ER to other membranes with comparably lower PtdIns concentrations, such as the plasma membrane.159 A specific subclass of PITPs are type 1 START-like PITPs that encompass three main isoforms: PITPα, PITPβ and RdgBβ.159 PITPα is arguably the best-characterised isoform, and most widely associated with disease pathology due to its high affinity for PtdIns binding.159 For instance, PITPα is required for normal neuronal development by regulating the co-ordinated accumulation of PtdIns to the leading edge of axons, thus ultimately contributing to localised PIP3 generation, by PI3K-enhanced AKT signalling, and axon elongation.160 An integral role for PITPα in promoting signal transduction pathways initiated by RTKs has also been described in the context of EGFR activation, suggesting that PITPα could also be closely associated with oncogenic signalling.161 This probably involves the PITPα-mediated provision of PtdIns to the plasma membrane, leading to the localised accumulation of a phosphoinositide pool at activated RTKs and downstream synthesis of mono-, di- and triphosphorylated phosphoinositide secondary messengers.161 Interestingly, PITPα has also been implicated in tumour metastasis through an intricate mechanism linking PIP2 and inositol 1,4,5-triphosphate (IP3) signalling in platelet cells.162 In this model, PIPTα drives the formation of a specific pool of PIP2 that is utilised for IP3 synthesis through enhanced phospholipase Cγ (PLCγ) activity.162 A major implication of this PIPTα–PIP2–IP3 signalling axis is the production of thrombin by platelets, allowing them to adhere to circulating tumour cells and facilitating their dissemination to distant tissues.162 Overall, these findings illustrate that dysregulated FA metabolism in the form of aberrant transport and localisation of lipid molecules, namely PtdIns, has notable effects on the spatial production of secondary messengers that ultimately impact on cell-signalling pathways.

In terms of phosphoinositide metabolism, growth-factor stimulation promotes the synthesis of PIP3 within seconds, leading to the rapid induction of PI3K–AKT signalling. This implies the existence of a highly co-ordinated enzymatic system that can efficiently catalyse the conversion of membrane-localised pools of PtdIns into pro-tumorigenic phosphoinositides. Indeed, the scaffold protein IQGAP1 is essential in this process, as it can simultaneously bind PI4KIIIα, PIPKIα and PI3K to facilitate the sequential synthesis of PI(4)P, PI(4,5)P2 and PI(3,4,5)P3 from PtdIns, respectively.163 It is well accepted that PIP2 is present in excess of up to 100-fold when compared with PIP3 at the plasma membrane, even in stimulated cells.164 Therefore, the spatial regulation of PIP3 generation mediated by IQGAP1 – which, in turn, is dependent on the presence of localised pools of PIP2 and PtdIns at sites of activated RTKs – could represent the rate-limiting step in the efficient synthesis of this secondary messenger, as opposed to the general supply of FAs per se.163

In addition to PtdIns, PAs can serve as potent signalling molecules. The predominant source of PAs is from the hydrolysis of PC and PE by phospholipase D 1/2 (PLD1/2); however, glycerol-3-phosphate (G3P) can also be used as a substrate for glycerol-3-phosphate acyltransferase (GPATs) to synthesise PA.165 Notably, PAs can directly bind and stabilise mTOR, thus leading to increased activity of both mTORC1 and mTORC2.166 Inhibition of PA synthesis reduces mTORC2-dependent phosphorylation of AKT on Ser473, suggesting that mTOR, in addition to sensing nutrients including amino acids,167,168 also integrates signals from lipids to ultimately coordinate cellular growth and proliferation.169 It is particularly interesting to note that PAs can directly compete with mTOR inhibitors such as rapamycin for binding to the mTOR complexes.169 This finding may have important clinical implications, as it suggests that the levels of PA and the activity of enzymes involved in its synthesis, such as PLD and GPAT, could influence sensitivity to mTOR inhibition.169

Bioactive lipids can also stimulate cell proliferation through autocrine and paracrine mechanisms that require the activation of G-protein-coupled receptors (GPCRs) (Fig. 5). Among the most potent of these lipid species are lysophosphatidic acids (LPAs) consisting of a phosphate head group attached to a glycerol backbone and a single FA tail.170 The production of LPA is influenced by the abundance of various lipid species. For instance, LPA can be generated through two main mechanisms: the first involves cleavage of existing phospholipids at the sn-2 position by phospholipases (PLAs) to release a lysophospholipid and a FA, and the second requires the lysophospholipase D activity of autotaxin to convert LPC into LPA extracellularly.171 In terms of the first mechanism in particular, cells must have increased synthesis of PA that specifically releases LPA following cleavage by phospholipases. In this context, a dominant role for PLD2 has been described, with gastric, breast and colorectal cancers displaying elevated protein expression‎ and activity.172 Moreover, DAG can directly contribute to the cellular pool of PA through the enzymatic activity of DAG kinases (DGKs).173 Notably, DGKα has been shown to promote the synthesis of PA from DAG, which can subsequently be used to generate LPA in fibrotic tissues, thus negatively impacting the efficacy of radiation therapy.174 Therefore, dysregulated lipid metabolism can directly regulate the generation of LPA by modulating the cellular pool of PA. The latter is also activated by CDP to form CDP–DAG that can then be converted into glycerophospholipids PtdIns, PG and cardiolipin. Importantly, this biosynthetic pathway demonstrates how changes in LPA and/or PA might play a crucial role in regulating intracellular signalling and trafficking by affecting the pool of PI, which acts as the major precursor of all phosphoinositides.

Fig. 5

Remodelling of the tumour microenvironment by bioactive lipids. Eicosanoids and lysophosphatidic acid species can be secreted into the surrounding microenvironment and stimulate cell proliferation through both autocrine and paracrine mechanisms. Arachidonic acid (AA) serves as the main precursor for eicosanoid synthesis, and these include pro-inflammatory prostaglandins, leukotrienes and eicosatetraenoic acids. PGE2 can stimulate cell proliferation through autocrine and paracrine signalling, and this is largely mediated through the activation of EP1–EP4 receptors. Moreover, prostaglandins contribute to immunosuppression by attenuating the activation of natural killer, dendritic and cytotoxic T cells. Lysophosphatidic acids are also relevant signalling molecules, and can be produced intracellularly from glycerol-3-phosphate or phosphatidic acid, or extracellularly through the enzyme autotaxin, which uses existing phospholipids, such as phosphatidylglycerols and phosphatidylethanolamines as substrates. Similar to eicosanoids, lysophosphatidic acids exert their tumorigenic effects by binding to the LPAR family of G-protein-coupled receptors.

Abbreviations: RTK, receptor tyrosine kinase; LOX, lipoxygenase; COX, cyclo-oxygenase; PGG2, prostaglandin G2; PGH2, prostaglandin H2; PGE2, prostaglandin E2; PGI2, prostaglandin I2; TXA2, thromboxane A2; HETE, hydroxytetraenoic acid; EP, prostaglandin E2 receptor; NK, natural killer cell; G3P, glyceraldehyde 3-phosphate; GPAT, glycerol-3-phosphate acyltransferase; PA, phosphatidic acid; PLA2, phospholipase A2; LPA, lysophosphatidic acid; LPAR, lysophosphatidic acid receptor; ATX, autotaxin.

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Several LPA species containing FA tails of varying carbon length and desaturation exist, with the most common and biologically relevant being LPA(16:0) and LPA(18:1).175 Human cells express six LPA receptor (LPAR) genes encoding LPAR1–6 to which LPAs bind and exert their pro-tumorigenic effects.170 These include activation of PI3K and Ras–MAPK signalling that have well-established roles in driving cell proliferation by inhibiting negative regulators of cell-cycle progression such as p21, p27 and p15, as well as induction of RHO GTPases that promote cell migration through remodelling of the actin cytoskeleton.176,177,178 LPAs are also implicated in autocrine and paracrine-signalling networks, thus serving as important intermediaries between tumour cells and the microenvironment. Indeed, in pancreatic ductal adenocarcinomas (PDAC), pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) display elevated synthesis of LPCs from glucose and glutamine, and ultimately release these lysophospholipids into the surrounding microenvironment.179 PDAC cells display increased secreted levels of autotaxin, facilitating the rapid and localised conversion of LPC into LPA, and consequent activation of AKT signalling through stimulation of LPAR1/2.179 Pharmacological inhibition of autotaxin significantly reduces PDAC tumour growth in vivo, and this effect is more pronounced following co-transplantation with PSCs, thus highlighting the importance of the latter in dynamic lipid remodelling through local LPC release and autotaxin-mediated conversion into LPA.179 These results also suggest that therapeutically targeting metabolic interdependencies between the primary tumour and the surrounding microenvironment could be an effective strategy for the treatment of PDAC.179

Eicosanoids remodel the tumour microenvironment

An important subclass of bioactive lipid molecules are eicosanoids. The omega-6 FA arachidonic acid (AA) serves as the main precursor of several eicosanoid species, including prostaglandins, thromboxanes and leukotrienes, each of which has pro-inflammatory and pro-tumorigenic effects.72 There are three main mechanisms through which cancer cells can obtain AA: (1) direct exogenous uptake by using specific transporters, such as CD36 and TWIK-related AA-stimulated K+ (TRAAK) channels, (2) de novo synthesis from linoleic acid (LA) and (3) cleavage of the sn-2 position of existing membrane phospholipids through the enzymatic activity of phospholipases. Each of these processes has been extensively reviewed previously.72,180 The predominant enzymes involved in prostaglandin production are the prostaglandin G/H synthetases COX1 (PTGS1) and COX2 (PTGS2). The former is constitutively active and regulates normal cellular processes including angiogenesis and blood clotting, whilst COX2 expression‎ is selectively induced by growth factors and chemokines, and is, therefore, more closely linked with inflammation.72 The cyclo-oxygenase and peroxidase activities of COX enzymes sequentially convert AA into prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2), respectively.72 Other eicosanoids including PGE2, PGD2, prostacyclins and thromboxanes can be derived from PGH2.72

Prostaglandins exert pro-inflammatory and pro-tumorigenic effects in both autocrine and paracrine fashions by activating G-protein-coupled prostanoid receptors including EP1–4, DP1, PGF receptor (FP), PGI receptor (IP) and TX receptor (TP) (Fig. 5).181 Tumour-initiating events triggered by prostaglandins include PGE2-mediated activation of PI3K signalling and induction of ERK following binding to the EP4 receptor, thus stimulating proliferation, as well as cell migration through stabilisation of β-catenin and c-MET induction.182,183 In addition, in models of colorectal cancer, intracellular PGE2 can induce phosphorylation and activation of EGFR, leading to induction of MMPs and a consequent promotion of cell invasiveness.184 Prostaglandins can also promote adaptation to microenvironmental stress conditions such as hypoxia.185 Under hypoxic conditions, HIF1α induces the expression‎ of COX2, leading to a concomitant overproduction of PGE2 that stimulates tumour angiogenesis in a VEGF- and chemokine (c–X–c motif) ligand 1 (CXCL1)-dependent manner.186,187 It is interesting to note that at least in colorectal cancer, HIF1 can actually induce cell-cycle arrest by binding to β-catenin and displacing transcription factor 4 (TCF4), thereby blocking the formation of a functional β-catenin–TCF4 transcriptional complex and inhibiting the transcription of genes involved in proliferation.185,188 This mechanism is particularly intricate because it demonstrates how the crosstalk between HIF and prostaglandin signalling can induce a ‘hibernation’ state in cancer cells that is characterised by sustained nutrient acquisition through vascularisation, and reduced energy expenditure.185,188 The main implications of this could be that cancer cells are better equipped to recover from hypoxia and resume proliferation immediately following reoxygenation.

Further to the direct effects on tumour cells, prostaglandins can also modulate the surrounding microenvironment, and this has been extensively demonstrated in the context of inhibition of the anti-tumour immune response (Fig. 5). One mechanism through which elevated PGE2 promotes tumour immune evasion is by abrogating co-stimulation and complete activation of CD8+ T lymphocytes mediated by binding of intercellular adhesion molecule 1 (ICAM-1) expressed on tumour cells and the lymphocyte receptor LFA-1.189 In addition, accumulation of conventional type 1 dendritic cells (cDC1s) is essential for initiating the anti-tumour immune response, and requires the infiltration of natural killer cells within the tumour microenvironment.190 However, in models of BRAFV600E mutant melanomas, overproduction of COX2-derived PGE2 directly inhibits the production of CXCL1 and chemokine (c–C motif ligand 5 (CCL5) chemokines by natural killer (NK)) cells, thereby attenuating the migration of cDC1s to the tumour site.190 Importantly, the accumulation of NK and cDC1 cells is associated with better prognosis in melanoma and breast cancers, indicating that the immunomodulatory properties of prostaglandins could have significant clinical implications.190 Indeed, the response of melanomas harbouring BRAFV600E mutation to anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors is significantly improved following combinatorial therapy with COX inhibitors including aspirin and celecoxib.191

An additional pathway for AA metabolism is its conversion into arachidonyl-CoA following the ligation of acetyl-CoA catalysed by the acyl-CoA synthetase ACSL4.192 Arachidonyl-CoA can be subsequently esterified to form TAGs and incorporated into phospholipids, or utilised as a substrate by COX2 to enhance eicosanoid biosynthesis.193 ACSL4 is also implicated in the localised release of AA in the mitochondria, and this requires the transport of arachidonyl-CoA to the inner mitochondrial membrane via the translocator protein (TSPO) and hydrolysis by acyl-CoA thioesterase 2 (ACOT2).192 Importantly, several studies have implicated ACSL4 in tumorigenesis, with advanced-stage breast, colorectal, hepatocellular and prostate carcinomas displaying increased expression‎ at both the mRNA and protein levels.192 The oncogenic effects of elevated ACSL4 are twofold. Firstly, mitochondrial AA that accumulates as a consequence of ACSL4 activity is predominantly directed towards the biosynthesis of leukotrienes including 5-, 12- and 15-hydroxyeicosatetraenoic acid (HETE).194 These metabolites potently activate leukotriene B4 receptors and potentiate several oncogenic signalling pathways including PI3K–AKT and Wnt–β-catenin, thus promoting cell migration and proliferation in breast and prostate cancer cells.194 Secondly, the excessive accumulation of unesterified polyunsaturated FAs (PUFAs) promotes apoptosis through induction of the ER-stress response, activation of caspase-3 and tumour necrosis factor α (TNFα) signalling.195 ACSL4 limits the cytotoxicity associated with elevated cellular pools of unesterified AA by producing arachidonyl-CoA, thereby increasing the apoptotic threshold and survival of castration-resistant prostate cancer (CRPC) cells.192 It is important to note, however, that the localised accumulation of arachidonyl-CoA and AA in the mitochondria can also contribute to membrane depolarisation and electron transport chain uncoupling, leading to increased ROS production.196 If left unchecked, the elevation in ROS levels can increase lipid peroxidation and cell death induced by ferroptosis.196 Thus, cancer cells must also have adequate anti-oxidative responses, including increased Nrf2 activity and NADPH/glutathione biosynthesis, to capitalise on the pro-tumorigenic effects of ACSL4 overexpression‎.

Therapeutically exploiting fatty acid metabolism in cancer

Given the extensive role of FAs in cancer pathogenesis, there is substantial clinical interest in developing therapies that target FA metabolic reprogramming. The majority of inhibitors designed for this purpose target specific enzymes involved in de novo FA synthesis and exogenous lipid uptake (Table 1); however, there is also a resurgent interest in understanding how specific dietary interventions may synergistically improve the efficacy of existing cancer therapeutics. Current strategies and considerations for successfully targeting the tumour lipidome are discussed below.

Table 1 Non-exhaustive list of therapies targeting lipid metabolism as cited in the main text.

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Targeting FASN: a challenging past but promising future

In terms of therapeutically targeting dysregulated lipid metabolism in cancer, FASN has arguably received the most widespread interest, and this is not surprising given its multifaceted roles in supporting both anabolic metabolism and oncogenic signalling. However, the transition of FASN inhibitors from bench to bedside has largely been elusive, and marked with several challenges and shortcomings. This is particularly relevant for the first-generation FASN-targeting drugs, such as C75, orlistat and cerulenin. These compounds initially showed great promise in preclinical studies, with both significantly reducing tumour xenograft growth and inducing cell-cycle arrest, whilst also sensitising breast cancer cells to ROS-inducing chemotherapies by decreasing the synthesis of saturated lipids.102,197,198 In spite of these successful outcomes in the laboratory, significant clinical obstacles included detrimental systemic side effects characterised by drastic weight loss and anorexia,199 thus highlighting the involvement of FA metabolic enzymes in both disease pathology and normal whole-body metabolic homoeostasis. Indeed, recent studies have demonstrated that in both normal and malignant ovarian models, FASN expression‎ largely reflects the proliferative and growth state of a cell, rather than malignancy per se.200 Interestingly, proliferative non-malignant ovarian surface epithelial (OSE) and fallopian tube secretory epithelial (FT) cells express levels of FASN comparable with ovarian cancer cell lines, and display similar sensitivities to FASN inhibition by C75 and G28UCM.200 These observations, however, do need to be reconciled with the commonly held notion that elevated de novo lipogenesis driven by FASN is a metabolic hallmark of cancer, but not normal cells, and therefore, the latter should be largely insensitive to FASN inhibition. Previous studies demonstrating that FASN-catalysed endogenous FA synthesis in normal liver and adipose tissue is actually stimulated by a high-carbohydrate diet not only add another layer of complexity to this notion, but also suggest that monitoring nutrient availability may be indispensable in determining the whole-body sensitivity of noncancerous cells to FASN inhibition.201 Thus, in terms of clinical implications, it will be important to characterise FASN as a potential general proliferative marker – rather than being solely associated with malignancy – as well as understanding the effects of nutrition on the dependence of normal tissues for FASN-driven lipogenesis.

More recently, next-generation FASN inhibitors, including TVB-3166 and TVB-2640, have shown tremendous anti-tumour potential in preclinical breast and colorectal cancer models, as well as excellent tolerability and limited systemic toxicity in early-phase clinical trials.202,203 One explanation for the improved tolerance of the next-generation inhibitors could be that in contrast to C75 and cerulenin, TVB-3166 and TVB-2640 do not contribute to the indirect activation of CPT1 in peripheral tissue.202 The induction of β-oxidation peripherally following C75 or cerulenin treatment contributes to increased energy expenditure, loss of adipose tissue and significant weight loss, whereas next-generation inhibitors display higher specificity for FASN with limited off-target effects.202,204 Accompanying the development of novel FASN therapies is a concerted effort to better stratify patients who will actually benefit from FASN inhibition. A potential strategy for this endeavour may include assessment of HER2 status, particularly in light of the connections between FASN expression‎ and signalling downstream of HER2, which have been discussed earlier in this review.82 Indeed, there are now two clinical trials in Phase 2 stages eval‎uating the combinatorial effects of TVB-2640 and chemotherapy in HER2-positive breast cancer (Clinical Trial ID: NCT03179904) and astrocytomas (Clinical Trial ID: NCT03032484).205

Targeting ACLY and ACSS2: limiting the metabolic substrates for lipogenesis

Increased expression‎ and activity of ACLY is observed across several tumour types including glioblastoma, colorectal, breast and hepatocellular carcinomas.34 Considering its role in generating acetyl-CoA, which is the main substrate for lipogenesis and cholesterol synthesis, targeting ACLY has proven to be an effective therapy for treating hypercholesterolaemia and hyperlipidaemia.206 Importantly, several ACLY inhibitors including ETC-1002 (Phase 2/3 clinical trials) and hydroxycitrate (randomised control trials) have shown high efficacy in lowering low-density lipoprotein–cholesterol and good tolerability in patients with cardiovascular disease and type 2 diabetes (Table 1), thus indicating that ACLY inhibition could represent a well-tolerated therapeutic strategy.207,208,209,210,211

There is considerable interest in ACLY as a target for anticancer drugs; however, clinical trial studies in this context are far more limited when compared with dyslipidaemia cases. Nevertheless, there is a plethora of preclinical evidence to support the integral role of ACLY in tumorigenesis and the potential clinical benefits for its selective inhibition. In particular, both genetic and pharmacological targeting of ACLY significantly reduces the growth of lung and prostate tumour xenografts, and this anti-tumorigenic effect is more pronounced in highly glycolytic cells.34 Perhaps this is not surprising given that ACLY largely generates acetyl-CoA from glucose-derived citrate, but it does suggest that metabolic stratification of tumours may improve the potency of ACLY inhibitors such as SB-204990 and hydroxycitrate.34 This is particularly relevant when one considers the current limitations of ACLY-targeted cancer therapeutics, which predominantly include the relatively high drug concentrations required for complete inhibition of ACLY activity. Thus, by identifying tumours with high rates of glucose consumption that are consequently more dependent on ACLY activity for glycolysis-fuelled lipogenesis, dosing regimes with lower drug concentrations could be implemented.34 Furthermore, structural studies focussing on characterising the protein domains of the ACLY tetramer have revealed novel hydrophobic regions near the citrate-binding site that have untapped potential for improving the drugability of ACLY.212

Another approach for implementing ACLY inhibition as a therapeutic strategy for cancer is to consider its role in signalling networks that regulate cellular responses to energy stress. For instance, in CRPC cells, inhibition of ACLY disrupts ER and energy homoeostasis in CRPC cells, leading to AMPK activation and sensitisation to androgen receptor inhibitors.213 Intriguingly, supplementation of exogenous FAs is sufficient to restore hormone resistance in CRPC cells by alleviating the ER and energy stress instigated by ACLY inhibition, demonstrating the importance of an ACLY–AMPK network in regulating energy homoeostasis that could be exploited pharmacologically.213 Indeed, several AMPK-activating therapies such as metformin have shown anticancer and anti-inflammatory properties, and importantly are well tolerated in patients.214 Notably, some ACLY inhibitors currently used for the treatment of hypercholesterolaemia, such as ETC-1002, are also dual activators of AMPK, and although not yet investigated, it would be interesting to assess the applicability of these drugs in the cancer therapy context.207 While dual targeting of ACLY and AMPK does seem like an attractive therapeutic strategy, it is necessary to acknowledge the instances in which the latter may actually promote tumorigenesis. For instance, the presence of functional LKB1 is essential for complete AMPK activation, and given that this kinase is frequently mutated – including in 34% of lung carcinomas and 20% of cervical cancers – it may be necessary to first stratify patients based on LKB1 status to eval‎uate the true therapeutic potential of AMPK activators.215 Furthermore, the extent of mTORC1 hyperactivation should also be considered, as tumours that are dependent on mTOR signalling are more likely to have a better response to AMPK activation.214 Closely linked with this idea are the regulatory feedback mechanisms that exist between mTORC1 and mTORC2–AMPK is a well-characterised negative regulator of mTORC1; however, the potential compensatory effects leading to mTORC2 hyperactivation and initiation of pro-tumorigenic signalling, such as induction of AKT, must be carefully considered.214 Finally, AMPK activation promotes calcium-induced migration of prostate cancer cells through calmodulin-dependent protein kinase (CaMKKB) signalling.216 Thus, it appears that therapeutically exploiting ACLY and AMPK activities requires extensive molecular characterisation of a patient’s tumour, and may be context-dependent.

Although the effects of ACLY inhibition predominantly focus on FA synthesis, an additional biological feature of reducing acetyl-CoA synthesis is remodelling histone acetylation and gene expression‎ patterns.135 Given the essentiality of acetyl-CoA in other metabolic pathways and gene regulation, it may be necessary to undertake parallel transcriptomic and metabolomic profiling of adjacent normal tissue in order to fully ascertain the systemic consequences of inhibiting acetyl-CoA production. To improve the selective modulation of acetyl-CoA production in tumour cells, whilst simultaneously sparing healthy tissue, an alternative strategy could be to exploit therapeutic windows arising from the plasticity of cancer cells in metabolically challenging microenvironments. With regard to acetyl-CoA metabolism, tumours specifically upregulate ACSS2 under conditions of hypoxia or lipid deprivation, leading to increased acetate uptake and ligation with CoA to produce acetyl-CoA for de novo lipogenesis.33 Importantly, a HIF–SREBF2 signalling axis drives ACSS2 expression‎ and confers exquisite sensitivity to its inhibition in hypoxic or otherwise metabolically stressed tumours.33 Although the development of ACSS2-specific inhibitors is lagging considerably behind ACLY-targeted therapies, efforts are being made to bridge this gap through identification of novel selective inhibitors by using high-throughput screens.217 In fact, one of the most potent compounds identified, N-(2,3-di-2-thienyl-6-quinoxalinyl)-N'-(2-methoxyethyl)urea, has already been shown to sensitise chemotherapy-resistant bladder cancers that are dependent on acetate metabolism to cisplatin.217,218

Targeting SCD: inhibiting fatty acid desaturation

Desaturation of FAs by SCD enzymes produces monounsaturated FAs that contribute to the synthesis of additional lipid species including glycerophospholipids and sphingolipids.56 Ectopic SCD expression‎ promotes EMT and is associated with poor prognosis in breast and colorectal cancer.56 This provides a therapeutic opportunity for tumours that depend on canonical SCD-mediated desaturation, and the effect is more apparent in the absence of exogenous lipids.55 SCD inhibitors, such as SSI-4, betulinic acid (BetA) and MF-438, have been shown to induce apoptosis in cancer cells through multiple mechanisms including induction of the ER-stress response, modulating mitochondrial dynamics by altering cardiolipin structure, and growth inhibition of cancer stem cells (Table 1).55,56,219,220,221 Interestingly, not all cancers display sensitivity to SCD inhibition, as they rely on a compensatory desaturation pathway by utilising FADS2 to generate sapienate from palmitate.57 In this context, sapienate, instead of palmitoleate generated from SCD, contributes substantially to membrane synthesis in hepatocellular and lung carcinomas.57 As a result, a significant reduction in tumour area is only observed following combinatorial treatment of hepatocellular carcinoma xenografts with SCD and FADS2 inhibitors, thereby blocking any compensatory pathways for obtaining desaturated FAs.57 In light of these findings, it is important to consider that the canonical function of FADS2 is the desaturation of LA to γ-linolenic acid (C18:3n6).180 Given that FADS2 is obligatory for the de novo synthesis of long-chain omega-6 FAs including AA, it would be interesting to further investigate the potential regulatory mechanisms and microenvironmental conditions that determine the substrate preference of FADS2. This could yield significant insight into the interplay of sapienate metabolism with other FA biosynthetic pathways, and in turn uncover additional compensatory mechanisms that can be exploited therapeutically.

Dietary interventions and cancer therapeutics

Finally, there has been a resurgent interest in studying the role of dietary interventions in cancer therapy.76,222,223 For instance, it has been demonstrated that a low-carbohydrate ketogenic diet dramatically increases the efficiency of PI3K inhibitors and synergistically reduces the growth of PIK3CA-mutant tumours.76 Since humans can only obtain essential omega-3 and omega-6 FAs from the diet, it is tempting to speculate that dietary modifications based on lipid consumption could also have an impact on tumorigenesis. Omega-3 FAs, including eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively), are widely accepted to have anti-inflammatory properties by competing with AA for COX2 binding, and subsequently producing PGE3 instead of PGE2.224 In contrast, omega-6 FAs, such as LA and AA, are the precursors for pro-inflammatory eicosanoids.225 The recommended dietary ratio of omega-6:3 FAs is 1:1; however, the Western diet, which is significantly enriched in omega-6s, has a ratio of 15:1,225 and this has significant implications for the progression of several cancers including breast and colorectal.226 Conversely, a diet rich in omega-3 FAs has been associated with the pathological improvement of several inflammatory diseases, such as arthritis and asthma224,227,228 (Table 1), as well as reduced risks of developing breast, colorectal and prostate cancers.224,229 It is important to note, however, that excessive omega-3 consumption can also have undesirable side effects including immunosuppression.230 Therefore, it is essential that careful optimisation of omega-3:omega-6 ratios is undertaken for each patient. By taking these factors into account, modulation of dietary fat intake either alone or in combination with existing therapies could have tremendous potential in therapy response.

Conclusions and future perspectives

It is now widely appreciated that cancer cells display significant rewiring in their FA metabolism. This is not surprising when one considers the intricate regulation of lipid homoeostasis in the context of oncogenic signalling pathways, such as PI3K–AKT–mTOR and their diverse cellular functions. These are not just limited to cell intrinsic processes, such as membrane synthesis or serving as intracellular secondary messengers, but also extend to remodelling of the entire tumour microenvironment through paracrine-signalling mechanisms. In terms of therapeutic strategies, it is unlikely that inhibiting single enzymes or pathways will be sufficient to harness the full potential of targeting FA metabolism in cancer treatment. Instead, it is necessary to consider the complex framework within which FAs and their by-products are synthesised and exert their functions, including the activation of various compensatory pathways that sustain FA metabolism, and dynamic interactions with the tumour microenvironment and nutrient availability. This area of research holds great promise for the implementation of novel combinatorial strategies that exploit the unique dependency of cancer cells on FAs, both through pharmacological inhibition of metabolic targets and dietary interventions.

식이 요법과 암 치료법

최근에 암 치료에서

식이 요법의 역할을 연구하는 데 대한 관심이 다시 높아지고 있습니다. 76,222,223

예를 들어,

저탄수화물 케톤 생성 식단이 PI3K 억제제의 효능을 현저히 증가시키고

PIK3CA-변이 종양의 성장 을 시너지적으로 감소시킨다는 것이 입증되었습니다.76

인간은

필수 오메가-3 및 오메가-6 지방산을 식이로부터만 얻을 수 있기 때문에,

지방 섭취를 기반으로 한 식이 조절이 종양 발생에 영향을 미칠 수 있다는 추측이 제기되고 있습니다.

오메가-3 지방산(EPA와 DHA)은

AA와 COX2 결합을 경쟁하여 PGE3 대신 PGE2를 생성함으로써

항염증 효과를 갖는 것으로 널리 인정됩니다. 224

반면,

리놀레산(LA)과 아라키돈산(AA)과 같은 오메가-6 지방산은

염증성 에이코사노이드의 전구체입니다.225

오메가-6:3 지방산의 권장 식이 비율은 1:1이지만,

오메가-6가 풍부한 서구 식단은 15:1의 비율을 보이며,

이는 유방암과 대장암을 포함한 여러 암의 진행에 중요한 영향을 미칩니다. 226

반면,

오메가-3 지방산이 풍부한 식단은 관절염과 천식 등

여러 염증성 질환의 병리학적 개선224,227,228 (표 1)과

유방암, 대장암, 전립선암 발병 위험 감소와 연관되어 있습니다.224,229

그러나

과도한 오메가-3 섭취는 면역 억제 등

부작용을 유발할 수 있다는 점을 주의해야 합니다. 230

따라서

각 환자에게 맞춤형으로 오메가-3:오메가-6 비율을 최적화하는 것이 필수적입니다.

이러한 요소를 고려하여

식이 지방 섭취를 단독으로 또는 기존 치료법과 결합하여 조절하는 것은

치료 반응에 엄청난 잠재력을 가질 수 있습니다.

결론 및 미래 전망

암 세포가

지방산 대사에서 상당한 재편성을 보인다는 것은

이제 널리 인정되고 있습니다.

이는 PI3K–AKT–mTOR와 같은 종양 발생 신호 전달 경로에서

지방 균형의 복잡한 조절과 그 다양한 세포 기능 고려 시 놀랍지 않습니다.

이러한 변화는

세포 내 과정(예: 세포막 합성 또는 세포 내 2차 신호 전달체 역할)에 국한되지 않고,

파라크린 신호 전달 메커니즘을 통해 종양 미세환경의 전체 재편성까지 확장됩니다.

치료 전략 측면에서,

단일 효소나 경로를 억제하는 것만으로는

지방산 대사 표적 치료의 잠재력을 완전히 발휘하기 어려울 것입니다.

대신,

지방산과 그 대사산물이 합성되고 기능을 발휘하는 복잡한 프레임워크를 고려해야 합니다.

이는 지방산 대사를 유지하는 다양한 보상 경로의 활성화와

종양 미세환경 및 영양소 가용성과의 동적 상호작용을 포함합니다.

이 연구 분야는

약리학적 억제나 식이 개입을 통해

암 세포의 지방산 의존성을 활용하는 새로운 조합 전략의 구현에 큰 잠재력을 지니고 있습니다.

References

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