Inhibition of Hepatocellular Carcinoma Progression by Forced Metabolic Re-Programming

Using two different mouse models of liver cancer, we have recently shown that the commonly observed metabolic switch from oxidative phosphorylation to glycolysis known as the Warburg effect is inevitably accompanied by a marked decrease in fatty acid oxidation (FAO) and an increase in the activity of pyruvate dehydrogenase, the enzyme linking glycolysis to the TCA cycle. We now show that the short-term implementation of either medium-chain or long-chain high fat diets (HFDs) just prior to the induction of c-Myc oncoprotein-driven hepatocellular carcinoma (HCC) nearly doubled survival. Mechanistically, HFDs forced tumors to become more reliant on fatty acids as an energy source, thus normalizing FAO and PDH activities. We extended these findings to eighteen different cancer cohorts patients by showing that some tumors with high ratios of FAO-related:glycolysis-related transcripts were associated with more favorable prognoses than those with low ratios. We also used t-SNE, a machine learning-based dimensionality reduction technique, to show in other human tumors that the expression patterns of transcripts encoding FAO-related proteins and enzymes involved in cholesterol biosynthesis were also predictive of survival. Collectively, our results support the idea that tumors which are either forced to utilize fatty acids as an energy source or those which are already predisposed to doing so show significantly less aggressive behaviors. These findings suggest that short-tern dietary manipulation, either alone or in conjunction with more traditional chemotherapeutic regimens, might be employed as a relatively non-toxic and inexpensive means of enhancing survival in certain cancer types. Overall design: Total 6 groups Samples: Normal diets Liver( 5 samples), medium-chain (MC) high-fat diets Liver( 5 samples), long-chain (LC) high-fat dietsLiver( 5 samples), Normal diets Tumors(4 samples), medium-chain (MC) high-fat diets Tumors( 5 samples), long-chain (LC) high-fat diets tumors ( 5 samples),