When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

Abstract

The role of fatty acid metabolism, including both anabolic and catabolic reactions in cancer has gained increasing attention in recent years. Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis, therapeutic resistance and relapse. Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population. This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations. Therefore, these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters, which are often refractory to cancer treatment and difficult to target. Moreover, interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging. This review highlights recent findings on the relationship between fatty acid metabolism, cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

Keywords: Cancer cell plasticity; Cancer stem cells; Drug-tolerant persisters; Fatty acid metabolism; Fatty acid oxidation; Fatty acid synthesis; Lipogenic phenotype; Therapeutic resistance; Tumor-initiating cells.

Fig. 1

Fatty acid metabolism in cancer. Key enzymes involved in fatty acid (FA) metabolism. Orange-highlighted enzymes have been reported as altered in cancer or associated with cancer stemness. ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, ACSS2 acyl-CoA synthetase short-chain family member 2, FASN fatty acid synthase, CPT1/2 carnitine/palmitoyl-transferase 1/2, CACT carnitine acylcarnitine translocase, FAO fatty acid oxidation, IDH isocitrate dehydrogenase, TCA cycle tricarboxylic acid cycle, PDK pyruvate dehydrogenase kinase, PDH pyruvate dehydrogenase, P phosphorylation, U ubiquitylation, Ac acetylation

Fig. 2

Potential roles of fatty acid metabolism in regulating cancer cell plasticity. Cancer cells can be reprogrammed into a cancer stemness state or drug-tolerant state with appropriate cues. It has been shown that adipocytes in the tumor microenvironment secrete leptin, transforming growth factor β (TGFβ) or other hormones and growth factors that support conversion of cancer cells into more malignant cell types, including cancer stem cells/tumor-initiating cells or drug-tolerant persisters. Acetyl-CoA is a central hub for multiple metabolic pathways including FA synthesis and FAO. Therefore, acetyl-CoA might be a major carbon source for histone acetylation and regulating gene expression for reprogramming. ACSS2 is phosphorylated and transferred to nucleus for histone acetylation. Some transcription factors, including hypoxia inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3) and SMAD family member 2 (Smad2), are also involved in the conversion and may drive cancer cell plasticity