The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation

The Warburg effect is the long-standing riddle of cancer biology. How does aerobic glycolysis, inefficient in producing ATP, confer a growth advantage to cancer cells? A new evaluation of a large set of literature findings covering the Warburg effect and its yeast counterpart, the Crabtree effect, led to an innovative working hypothesis presented here. It holds that enhanced glycolysis partially inactivates oxidative phosphorylation to induce functional rewiring of a set of TCA cycle enzymes to generate new non-canonical metabolic pathways that sustain faster growth rates. The hypothesis has been structured by constructing two metabolic maps, one for cancer metabolism and the other for the yeast Crabtree effect. New lines of investigation, suggested by these maps, are discussed as instrumental in leading toward a better understanding of cancer biology in order to allow the development of more efficient metabolism-targeted anticancer drugs.