In oncology, the Warburg effect (/ˈvɑːrbʊərɡ/) is the observation that most cancers use aerobic glycolysis and lactic acid fermentation for energy generation rather than the mechanisms used by non-cancerous cells.
[1] This observation was first published by Otto Heinrich Warburg,[2] who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme".
While fermentation produces adenosine triphosphate (ATP) only in low yield compared to the citric acid cycle and oxidative phosphorylation of aerobic respiration, it allows proliferating cells to convert nutrients such as glucose and glutamine more efficiently into biomass by avoiding unnecessary catabolic oxidation of such nutrients into carbon dioxide, preserving carbon-carbon bonds and promoting anabolism.
[6] Warburg hypothesized that dysfunctional mitochondria may be the cause of the higher rate of glycolysis seen in tumor cells, as well as a predominant cause of cancer development.
However, most cancer cells predominantly release energy through a 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.
[6] 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.
In contrast, oxidative phosphorylation is associated with starvation metabolism and favored when nutrients are scarce and cells must maximize free energy extraction to survive.
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.
This is known as the “Warburg Effect.” The exact reasons for this are not fully understood, but it has been hypothesized that cancer cells create lactate to manage excess cytosolic electrons that the mitochondria cannot process.
[16] The enzymes involved in pyruvate metabolism prioritize: 1) efficient ATP production via mitochondrial oxidative phosphorylation, 2) disposal of excess cytosolic electrons as lactate, and 3) biosynthesis for growth.
[25] Dichloroacetic acid (DCA), a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, "downregulates" glycolysis in vitro and in vivo.
Through this mechanism of action, DCA works to counteract the increased production of lactate exhibited by tumor cells by enabling the TCA cycle to metabolize it by oxidative phosphorylation.
[35] The Warburg effect has served as a locus of popular misconceptions that cancer can be treated by reducing food and carbohydrate intake to supposedly "starve" tumours.