Aberrant lipid metabolism as a therapeutic target in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors. Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase. Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.

Keywords: Fatty acid; SCD1; hepatocellular carcinoma; lipid metabolism; lipids; liver cancer; stearoyl co-A desaturase.

Figure 1.

Fatty acid synthesis in HCC. Numerous role players in fatty acid biosynthesis are upregulated in HCC. Pyruvate is converted to citrate via the TCA cycle. ATP citrate lvase upregulated in HCC, catalyzes the conversion of citrate to cytosolic acetyl CoA and oxaloacetate. Acetyl CoA is converted to malonyl CoA via acetyl CoA carboxylase. FASN then combines malonyl CoA and acetyl CoA to form SFA. These SFA are converted to monosaturated fatty acids by SCDl.

Figure 2.

Other fatty acid metabolism targets. Upregulation of CD147 activates the AKT-mTOR signaling pathway, leading to increased expression of SREBPlc. Increased SREBPlc levels increases FASN and ACC expression, thus causing tumor growth and metastasis. Upregulation of CD147 also decreases PPAR α, which downregulates CPTlA and ACOXl. Tumor growth and metastasis results from downregulation of CPTlA and ACOXl. Decreased AMPK activity leads to tumor growth and metastasis by directly upregulating SREBPlc, FASN, and/or ACC. Decreased AMPK activity also downregulates CPTlA and ACOXl, thus leading to tumor growth and metastasis. Decreased KLF4 1evels leads to decreased MGLL activity, thus causing tumor growth and metastasis.