Fatty acid synthase: a druggable driver of breast cancer brain metastasis

Menéndez, Javier A.; Lupu, Ruth

doi:10.1080/14728222.2022.2077189

Cited by 14 publications

(11 citation statements)

References 199 publications

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“…Therefore, ACC1 produces malonyl‐CoA in the cytosol, which is the major carbon donor for fatty acid synthesis. Seven malonyl‐CoA molecules are used as the elongation unit, and together with acetyl‐CoA as the initiator, they are catalyzed by fatty acid synthase (FASN) to form one 16‐carbon saturated fatty acid, palmitate (Jones & Infante, 2015; Menendez & Lupu, 2022). By contrast, malonyl‐CoA synthesized by ACC2 is located near the mitochondrial surface and is thought to work as an inhibitor of carnitine palmitoyl transferase 1 (CPT1), thus regulating transport of long‐chain fatty acids into mitochondria for subsequent β‐oxidation (Wang et al , 2022).…”

Section: Introductionmentioning

confidence: 99%

Stearate‐derived very long‐chain fatty acids are indispensable to tumor growth

et al. 2022

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Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long‐chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long‐chain fatty acids (VLCFAs). Here, we show that depletion of acetyl‐CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth.

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Section: Introductionmentioning

confidence: 99%

Stearate‐derived very long‐chain fatty acids are indispensable to tumor growth

et al. 2022

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“…These results partially contradict the findings of previous studies. For instance, it has been demonstrated that FASN is substantially expressed in breast cancer-associated brain metastases, which are detrimental to the prognosis ( 43 , 53 , 54 ). Compared with extracranial tissues, the brain has much lower lipid content in multiple complex lipid species.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and clinicopathological significance of fatty acid synthase in breast cancer: A systematic review and meta-analysis

et al. 2023

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BackgroundAberrant expression of fatty acid synthase (FASN) was demonstrated in various tumors including breast cancer. A meta-analysis was conducted to investigate the role of FASN in breast cancer development and its potential prognostic significance.MethodsThe Web of Science, PubMed, Embase, and Cochrane Library databases were searched to identify studies that evaluated the relationship between FASN expression and overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS) of breast cancer patients. To analyze the clinicopathological and prognostic values of FASN expression in breast cancer, pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were clustered based on random-effects models. To confirm whether the findings were stable and impartial, a sensitivity analysis was performed, and publication bias was estimated. Data were analyzed using Engauge Digitizer version 5.4 and Stata version 15.0.ResultsFive studies involving 855 participants were included. Patients with higher FASN expression did not have a shorter survival period compared to those with lower FASN expression (summary HR: OS, 0.73 [95% CI, 0.41-1.32; P=0.300]; DFS/RFS, 1.65 [95% CI, 0.61-4.43; P=0.323]). However, increased FASN expression was correlated with large tumor size (OR, 2.04; 95% CI, 1.04-4.00; P=0.038), higher human epidermal growth factor receptor 2 (HER2) positivity (OR, 1.53; 95% CI, 1.05-2.23; P=0.028). No significant associations were observed between FASN expression and histological grade (OR, 0.92; 95% CI, 0.41-2.04; P=0.832), Tumor Node Metastasis (TNM) stage (OR, 1.11; 95% CI, 0.49-2.53; P=0.795), nodal metastasis (OR, 1.42; 95% CI, 0.84-2.38; P=0.183), Ki-67 labelling index (OR, 0.64; 95% CI, 0.15-2.63; P=0.533), estrogen receptor (ER) status (OR, 0.90; 95% CI, 0.61-1.32; P=0.586), or progesterone receptor (PR) status (OR, 0.67; 95% CI, 0.29-1.56; P=0.354).ConclusionFASN is associated with HER2 expression and may contribute to tumor growth, but it has no significant impact on the overall prognosis of breast cancer.

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“…FASN, a key enzyme in the initial stage of lipid synthesis, combines acetyl‐CoA with malonyl‐CoA and converts them into long‐chain FAs 92 . FASN has been demonstrated to be overexpressed in numerous solid and hematopoietic tumors, including non‐small‐cell lung cancer (NSCLC), 93 breast cancer, 94 pancreatic cancer, 95 and lymphoma 96 . TVB‐2640, the first FASN inhibitor to enter clinical research, displayed a gratifying tolerability profile with no significant gastrointestinal or serum chemical toxicity in a phase I clinical trial (NCT02223247).…”

Section: Inhibiting Ld Anabolism and Catabolism Is One Of The Approac...mentioning

confidence: 99%

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

Cui,

Man,

Tao

et al. 2024

Acta Physiologica

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IntroductionAbnormal lipid metabolism, one of the hallmarks in cancer, has gradually emerged as a novel target for cancer treatment. As organelles that store and release excess lipids, lipid droplets (LDs) resemble “gears” and facilitate cancer development in the body.AimThis review discusses the life cycle of LDs, the relationship between abnormal LDs and cancer hallmarks, and the application of LDs in theragnostic and clinical contexts to provide a contemporary understanding of the role of LDs in cancer.MethodsA systematic literature search was conducted in PubMed and SPORTDiscus. Retrieve and summarize clinical trials of drugs that target proteins associated with LD formation using the Clinical Trials website. Create a schematic diagram of lipid droplets in the tumor microenvironment using Adobe Illustrator.ConclusionAs one of the top ten hallmarks of cancer, abnormal lipid metabolism caused by excessive generation of LDs interrelates with other hallmarks. The crosstalk between excessive LDs and intracellular free fatty acids (FFAs) promotes an inflammatory environment that supports tumor growth. Moreover, LDs contribute to cancer metastasis and cell death resistance in vivo. Statins, as HMGCR inhibitors, are promising to be the pioneering commercially available anti‐cancer drugs that target LD formation.

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Fatty acid synthase: a druggable driver of breast cancer brain metastasis

Cited by 14 publications

References 199 publications

Stearate‐derived very long‐chain fatty acids are indispensable to tumor growth

Stearate‐derived very long‐chain fatty acids are indispensable to tumor growth

Prognostic and clinicopathological significance of fatty acid synthase in breast cancer: A systematic review and meta-analysis

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

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