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.
Highlights
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
Inhibition of CUB-domain-containing protein 1 (CDCP1) signifi- and are distinguished mainly through their associations of either cantly impairing the capacity of TNBCs to oxidise FAs stored in lipid droplets (LDs) Raptor in mTOR complex 1 (mTORC1), or during migration and metastasis.[67]
Inhibition of the mevalonate pathway with statins facilitates widespread effects on microRNA expression, reduced transcription of genes involved in folate metabolism such as dihydrofolate reductase (DHFR) as well as attenuation of histone deacetylases (HDACs) activity leading to CDKN1A promoter acetylation and transcription of the tumour suppressor p21.142 Overall, the activation of lipogenic enzymes such as fatty acid synthase (FASN), ATP–citrate lyase (ACLY) and acetyl-CoA synthetase 2 (ACSS2) are not just secondary events arising from hyperactive oncogenic signalling, but rather exist in a complex network involving reciprocal regulation
Summary
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. 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 serve as fuel sources for energy production. We will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (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.
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