Regulation Of Liver Cancer Survival By Lipid Metabolism During Metabolic Stress

Uncontrolled cell proliferation and the associated metabolic changes are commonattributes of cancers diverse in type and etiology. Alterations in fatty acid (FA)metabolism in cancer cells are increasingly receiving attention. Most cancer cells areprogrammed to glycolysis even in the presence of oxygen to produce cellular buildingblocks for cancer growth and proliferation-. Another commonly observed metabolicalteration in cancer is increased use of the amino acid glutamine to fuel anabolicprocesses. Both glycolysis and glutamine metabolism are critical for providingreduced NADPH in cancer cells, which is needed for lipid synthesis. While mostnormal human cells utilize exogenous lipid sources, cancer cells are adept at divertingcarbon from energy production to fatty acids (FA) for biosynthesis of membranes andsignaling molecules. It has been reported that up to60%of carbon skeletons fromglucose are used for de novo fatty acid synthesis (FAS) in cancer cells. Using in vivolabelling with14C-glucose, nearly all esterified FAs in tumor models were found to bederived from de novo synthesis.In addition to membrane lipid, fatty acids provide twice as much ATP ascarbohydrates, and in turn they are the preferred nutrient for storage under conditionsof nutrient abundance. Most cells store FAs in triglycerides (TGs) in the cytosoliclipid droplet (LD), an organelle whose major function is lipid storage. In contrast tonormal cells, de novo synthesis of FAs may account for more than90%oftriacylglycerol FAs in tumor cells. When necessary, fatty acids can be obtained fromhydrolysed triglycerides and catabolized by the fatty acid oxidation (FAO; alsoknown as β-oxidation) pathway. However, the relevance of FAO for cancer cellfunction has not been carefully examined.The terminal step of ATP-dependent FA biosynthesis is catalysed by themultifunctional fatty acid synthase (FASN). Overexpression of FASN is common tomany tumor cells and is often associated with poor prognosis, suggesting that fatty acid synthesis may contribute to increased survival and proliferation of tumor cells.Small molecule inhibitors of FASN, such as orlistat and C75, were shown topreferentially promote apoptosis of cancer cells compared to normal cells. On theother hand, carnitine palmitoyl transferase1(CPT1) is the first and rate-limiting stepof fatty acid transport into mitochondria for oxidation to carbon dioxide. It is yetunclear whether increased FAO in cancer cells will affect proliferation. CPT1C, anisoform of CPT1, was found to be upregulated in multiple cancer types and functionas a potential oncogene (GnD). By contrast, etomoxir (ETO), an inhibitor of CPT1,and ranolazine, an indirect inhibitor of FA oxidation, may kill cancer cells. These datasuggest that FAO functions are context dependent.Liver is the major site of de novo lipogenesis in the body, in which the extra FAsare stored in triglyceride droplets. Aberrant accumulation of lipid droplets into thehepatocytes results in hepatic steatosis, which contributes to the development ofhepatocellular carcinoma (HCC). Accordingly, a progressive induction of lipogenicenzymes including FASN has been described in nontumorous liver tissue toward theHCC, which is correlated with AKT-dependent cell proliferation.-On the other hand,FAO has been recently recognized as a key mechanism that promotes cancer cellsurvival during metabolic stress by enabling the production of ATP and NADPH.However, the precise roles of FAS and FAO in HCCs remain largely unknown.In this study, we demonstrate that HCC cells exhibit varied levels of TGs as aconsequence of glucose-derived de novo FAS, which are inversely correlated withsurvival capabilities of cells experiencing metabolic stress. FAS and FAO playdistinct roles in cells with or without metabolic stress via regulation of ATPavailability. Inhibition of FAO dramatically sensitizes HCC cells to chemotherapeuticdrugs. Our results suggest a new approach for HCC therapies based on manipulatingFA metabolism.