Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide, characterized by clinical aggressiveness, resistance to conventional chemotherapy, and high lethality. Consequently, there is an urgent need to better delineate the molecular pathogenesis of HCC to develop new preventive and therapeutic strategies against this deadly disease. Noticeably, emerging evidence indicates that proteins involved in lipid biosynthesis are important mediators along the development and progression of HCC in humans and rodents. Here, we provide a comprehensive overview of: (a) The pathogenetic relevance of lipogenic proteins involved in liver carcinogenesis, with a special emphasis on the master fatty acid regulator, fatty acid synthase (FASN); (b) The molecular mechanisms responsible for unrestrained activation of FASN and related fatty acid biosynthesis in HCC; (c) The findings in experimental mouse models of liver cancer and their possible clinical implications; (d) The existing potential therapies targeting FASN. A consistent body of data indicates that elevated levels of lipogenic proteins, including FASN, characterize human hepatocarcinogenesis and are predictive of poor prognosis of HCC patients. Pharmacological or genetic blockade of FASN is highly detrimental for the growth of HCC cells in both in vitro and in vivo models. In conclusion, FASN is involved in the molecular pathogenesis of HCC, where it plays a pivotal role both in tumor onset and progression. Thus, targeted inhibition of FASN and related lipogenesis could be a potentially relevant treatment for human HCC.

Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis

“…Furthermore, TVB2640 is currently under evaluation, alone or in combination with other drugs, in non-small cell lung carcinoma, HER2-positive advanced breast cancer, colorectal cancer, and high-grade relapsed astrocytoma as well as in subjects with non-alcoholic steatohepatitis (NCT03808558, NCT03179904, NCT02980029, NCT03032484, and NCT03938246). In addition, it has been demonstrated in experimental models that FASN inhibitors synergize with multiple chemotherapeutic agents and that FASN blockade restores the sensitivity to chemotherapeutic drugs and targeted therapies [ 49 ]. Based on these encouraging data and in the light of the problems in directly targeting the c-MYC protooncogene, the use of FASN inhibitors might represent a valid therapeutic approach for HCC, at least in the tumor subset showing activation of c-MYC.…”

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment

“…Several reports in the literature have indicated the relevance of fatty acid synthesis in HCC [42–44]. Immunohistochemical staining showed that the key regulatory enzyme, the fatty acid synthase, was positively expressed in all 20 HCC patients studied, whereas the positive expression rate in tumor‐adjacent tissue was only 10% [43].…”

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

“…Cholesterol is generated by the mevalonate pathway, by condensation of two AcCoA molecules to form 3-HMGCoA, which is then reduced to form mevalonate, and then isoprenoid farnesyl-pyrophosphate. Several studies have shown that targeting the synthesis of cholesterol inhibits cancer cell proliferation and transformation (56).…”

“…When the intracellular levels of cholesterol are high, insulin-induced genes interact with SREBP-cleavage-activating proteins (SCAPs) to retain SREBP inactive precursors attached to the ER. When cholesterol levels are low, SCAPs facilitate the translocation SREBPs to the Golgi apparatus to be further processed releasing the active forms (56). SREBP1 promotes the expression of lipogenic genes; meanwhile, SREBP2 regulates the expression of genes involved in the synthesis, uptake, and efflux of cholesterol.…”