Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

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.

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…3C & S3C). Although ACSL1 and ACSL5 are isozymes with similar catalytic function, genetic knockout studies in mice showed that ACSL5 has a major role in fatty acid biosynthesis and deposition, while ACSL1's function is mostly involved in fatty acid oxidation 34 . A metabolic model based on bulk gene expression data would incorrectly assume that both enzymes are expressed by malignant cells, thus over-estimating the metabolic capabilities of malignant cells.…”

Reprogramming of fatty acid metabolism in cancer

“…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.…”

Biomarker expression analysis in different age groups revealed age was a risk factor for breast cancer

“…Through regulation of DNA and RNA metabolism, epigenetic modification of pyrimidine metabolism may affect cell cycle, proliferation, and differentiation, including micro-RNAs and noncoding RNAs (Fu & He, 2012). In general, it is believed that the correlation between abnormal metabolism and cancer involves the associations among obesity, inflammation, and cancer cell proliferation, invasion, and angiogenesis (Amiri et al, 2018;Tang, Zhou, Hooi, Jiang, & Lu, 2018). Furthermore, cell cycle can influence cancer progression through mitosis and proliferation of cancer cells (Bai et al, 2019).…”