Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

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

“…Indeed, there was no increase in Fasn expression in mouse HCCs induced by c-Met and gain of function mutant of β-Catenin (c-Met/β-Catenin) via hydrodynamic injection. Consistently, ablation of Fasn did not affect HCC growth in mice (35). For this purpose, reliable biomarkers able to uncover the patients who would presumably benefit from this therapeutic strategy should be identified.…”

“…Based on the body of evidence presented before, it can be envisaged that FASN inhibition might represent a potentially effective therapeutic strategy against human HCC (35). Several FASN inhibitors have been tested against cancer in preclinical studies, including cerulenin, Orlistat, C75, Fasnall, TVB-2640, and others (Figure 3).…”

“…Cerulenin was found to be active against numerous cancer cell lines and xenograft models; however, the highly reactive nature of the cysteine-reactive epoxide group and off-target activities hampered its clinical application (36). In particular, activation of β-oxidation and excessive energy expenditure, leading to weight-loss or anorexia, represented the major factors limiting the application of cerulenin in humans (35). Similar reasons prevented the clinical use of C-75, a synthetic inhibitor of FASN, which was also demonstrated to possess profound antineoplastic effects in experimental models, and to enhance radiation-induced apoptosis in prostate cancer cells, promoting cell cycle arrest in the G2/M phase (37)(38)(39).…”

Transcriptomic and Proteomic analysis of clear cell foci (CCF) in the human non-cirrhotic liver identifies several differentially expressed genes and proteins with functions in cancer cell biology and glycogen metabolism

“…Specifically, we found an increased glycogen storage, reduced glucose-6-phosphatase activity and upregulated enzymes of glycolysis and de novo lipogenesis, beta-oxidation as well as overexpression of the insulin receptor and activated AKT/mTOR and Ras/MAPK pathways in CCF from both human livers and the rat model [20]. Similiarly, in the mouse, hepatocarcinogenesis is associated with activation of the insulin/AKT/mTOR signaling pathway, the transcriptional regulator ChREBP [16,21], as well as the lipogenic pathway [18,22,23]. Although these data hint to several pathways and regulators, a comprehensive inventory of gene and protein expression in human CCF is missing.…”

Integrative analysis of the characteristic of lipid metabolism-related genes for the prognostic prediction of hepatocellular carcinoma

“…Numerous studies have been carried out to uncover the biological phenotypes and molecular classification of HCC on the basis of lipid metabolic patterns [9]. Fox example, the de novo fatty acid synthesis phenotype in tumor cells has been associated with up-regulated lipid-related genes at multiple levels, such as transcription, translation and post-translation modification, and enzyme activity, as well as the influence of these genes on oncogenes [10]. Moreover, molecular classification of HCC based on lipid metabolism-related genes reveals distinct tumor subtypes.…”