No abstract

Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Background:The integrated stress response (ISR) is necessary to help the tumor adapt to its microenvironment. Results: ATF4 activates a PEPCK-M-dependent pro-survival pathway under amino acid deprivation or ER stress (ISR) by binding to its proximal promoter. Conclusion: PEPCK-M participates in supportive adaptations of cancer cells under stress. Significance: A previously unappreciated role for PEPCK-M in cancer cells opens a therapeutic window and enhances our understanding of cancer metabolism.

Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in cMYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours significantly delays tumourigenesis, glutamine catabolism continues due to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated by glycolysis. Thus, co-inhibition of Gls1 and hexokinase *

OBJECTIVE-Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by Pck1) catalyzes the first committed step in gluconeogenesis. Extensive evidence demonstrates a direct correlation between PEPCK-C activity and glycemia control. Therefore, we aimed to evaluate the metabolic impact and their underlying mechanisms of knocking down hepatic PEPCK-C in a type 2 diabetic model. RESEARCH DESIGN AND METHODS-PEPCK-C gene targeting was achieved using adenovirus-transduced RNAi. The study assessed several clinical symptoms of diabetes and insulin signaling in peripheral tissues, in addition to changes in gene expression, protein, and metabolites in the liver. Liver bioenergetics was also evaluated.RESULTS-Treatment resulted in reduced PEPCK-C mRNA and protein. After treatment, improved glycemia and insulinemia, lower triglyceride, and higher total and HDL cholesterol were measured. Unsterified fatty acid accumulation was observed in the liver, in the absence of de novo lipogenesis. Despite hepatic lipidosis, treatment resulted in improved insulin signaling in the liver, muscle, and adipose tissue. O 2 consumption measurements in isolated hepatocytes demonstrated unaltered mitochondrial function and a consequent increased cellular energy charge. Key regulatory factors (FOXO1, hepatocyte nuclear factor-4␣, and peroxisome proliferator-activated receptor-␥ coactivator [PGC]-1␣) and enzymes (G6Pase) implicated in gluconeogenesis were downregulated after treatment. Finally, the levels of Sirt1, a redox-state sensor that modulates gluconeogenesis through PGC-1␣, were diminished. CONCLUSIONS-Our observations indicate that silencing PEPCK-C has direct impact on glycemia control and energy metabolism and provides new insights into the potential significance of the enzyme as a therapeutic target for the treatment of diabetes.