Fatty acid activation in carcinogenesis and cancer development: Essential roles of long-chain acyl-CoA synthetases

Abstract

The significance of fatty acid metabolism in cancer initiation and development is increasingly accepted by scientists and the public due to the high prevalence of overweight and obese individuals. Fatty acids have different turnovers in the body: Either breakdown into acetyl-CoA to aid ATP generation through catabolic metabolism or incorporation into triacylglycerol and phospholipid through anabolic metabolism. However, these two distinct pathways require a common initial step known as fatty acid activation. Long-chain acyl-CoA synthetases (ACSLs), which are responsible for activation of the most abundant long-chain fatty acids, are commonly deregulated in cancer. This deregulation is also associated with poor survival in patients with cancer. Fatty acids physiologically regulate ACSL expression, but cancer cells could hijack certain involved regulatory mechanisms to deregulate ACSLs. Among the five family isoforms, ACSL1 and ACSL4 are able to promote ungoverned cell growth, facilitate tumor invasion and evade programmed cell death, while ACSL3 may have relatively complex functions in different types of cancer. Notably, ACSL4 is also essential for the induction of ferroptosis (another form of programmed cell death) by facilitating arachidonic acid oxidation, which makes the enzyme a desirable cancer target. The present review thus evaluates the functions of deregulated ACSLs in cancer, the possible molecular mechanisms involved and the chemotherapeutic potentials to target ACSLs. A better understanding of the pathological effects of ACSLs in cancer and the involved molecular mechanisms will aid in delineating the exact role of fatty acid metabolism in cancer and designing precise cancer prevention and treatment strategies.

Keywords: cancer development; carcinogenesis; cell death; fatty acids; long-chain acyl-CoA synthetases; metabolism.

Figure 1.

Acyl-CoA synthetases-mediated fatty acid activation is involved in two distinct lipid metabolism pathways. ACSS, short-chain acyl-CoA synthetase; ACSM, medium-chain acyl-CoA synthetase; ACSL, long-chain acyl-CoA synthetase; ACSVL, very long-chain acyl-CoA synthetase.

Figure 2.

Subcullular localization and function of ACSL isoforms. ACSL members reside in different subcellular organelles to channel fatty acids into two distinct metabolic pathways. The white arrows refer to channeling to anabolic metabolism, while the black arrows refer to catabolic metabolism. ACSL, long-chain acyl-CoA synthetase.

Figure 3.

Deregulated ACSL expression in cancer. The expressional changes of individual ACSL isoforms in different types of cancer were summarized. The asterisk indicates statistically significant associations with poor cancer survival outcomes. ACSL, long-chain acyl-CoA synthetase.