high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Anaerobic glycolysis is less efficient than oxidative phosphorylation for producing adenosine triphosphate and leads to the increased generation of additional metabolites that may particularly benefit proliferating cells. The Warburg effect has been much studied, but its precise nature remains unclear, which hampers the beginning of any work that would explore its therapeutic potential. Otto Warburg postulated this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause. Driving forces Older hypotheses such as the Warburg hypothesis suggests the Warburg effect may simply be a consequence of damage to the mitochondria in cancer. It may also be an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria, which are involved in the cell's apoptosis program that kills cancer cells. Fermentation favors cell proliferation Since glycolysis provides most of the building blocks required for cell proliferation, both cancer cells and normal proliferating cells have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate. Inefficient ATP production is only a problem when nutrients are scarce, but anaerobic glycolysis is favored when nutrients are abundant. Anaerobic glycolysis favors anabolism and avoids oxidizing precious carbon-carbon bonds into carbon dioxide. In contrast, oxidative phosphorylation is associated with starvation metabolism and favored when nutrients are scarce and cells must maximize free energy extraction to survive. Such trade-offs can be theoretically associated with Giffen behavior in economics. Evidence attributes some of the high anaerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase responsible for driving the high glycolytic activity. In kidney cancer, this effect could be due to the presence of mutations in the von Hippel–Lindau tumor suppressor gene upregulating glycolytic enzymes, including the M2 splice isoform of pyruvate kinase. TP53 mutation hits energy metabolism and increases glycolysis in breast cancer. The Warburg effect is associated with glucose uptake and utilization, as this ties into how mitochondrial activity is regulated. The concern lies less in mitochondrial damage and more in the change in activity. On the other hand, tumor cells exhibit increased rates of glycolysis which can be explained