Otto Warburg was a pioneering biochemistry researcher who made substantial contributions to our early understanding of cancer metabolism. Warburg was awarded the Nobel Prize in Physiology or Medicine in 1931 for his discovery of cytochrome c oxidase, not for his work on cancer and the formulation of the Warburg hypothesis.
The Warburg effect is the reverse of the Pasteur effect (the inhibition of fermentation by O2) exhibited by cancer cells; alteration of the Pasteur effect in cancer is linked to prolyl hydroxylases and hypoxia-inducible factor (HIF).
Tumour suppressors and oncogenes converge on HIF to reverse the Pasteur effect and thereby induce the Warburg effect.
Cancer cells carry out aerobic glycolysis and respiration concurrently.
Tumour suppressors and oncogenes exert direct effects on metabolism: p53 promotes the pentose phosphate pathway and oxidative phosphorylation; MYC induces glycolysis and glutamine metabolism.
Mutations in metabolic enzymes, specifically isocitrate dehydrogenase 1 (IDH1) and IDH2 and other citric acid cycle enzymes, are causally linked to familial and spontaneous cancers.
Otto Warburg pioneered quantitative investigations of cancer cell metabolism, as well as photosynthesis and respiration. Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues, a phenomenon known as the Warburg effect. However, this increase in aerobic glycolysis in cancer cells is often erroneously thought to occur instead of mitochondrial respiration and has been misinterpreted as evidence for damage to respiration instead of damage to the regulation of glycolysis. In fact, many cancers exhibit the Warburg effect while retaining mitochondrial respiration. We re-examine Warburg's observations in relation to the current concepts of cancer metabolism as being intimately linked to alterations of mitochondrial DNA, oncogenes and tumour suppressors, and thus readily exploitable for cancer therapy.
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We thank John Eaton for instigating this collaborative Review. The authors' work is partially funded by US National Cancer Institute grants (C.V.D.), the Leukemia Lyphoma Society (C.V.D.) and an American Association for Cancer Research 'Stand Up To Cancer' translational grant (C.V.D.). We also acknowledge support by the Swiss Federal Institute of Technology Zurich (P.L.B. and W.H.K.).
C.V.D. is a consultant for Agios Pharmaceuticals, Inc. W.H.K. and P.L.B. declare no competing financial interests.
The metabolic process by which energy is produced in the presence of O2 through the oxidation of organic compounds (typically sugars) to CO2 and H2O by glycolysis, the citric acid cycle and oxidative phosphorylation.
A metabolic pathway that occurs in the cell cytoplasm and involves a sequence of ten enzymatic reactions. These reactions convert glucose to pyruvate and produce the high-energy compounds ATP and NADH.
- Pasteur effect
Pasteur's observation that yeast cells consume less sugar when grown in the presence of O2 than when grown in the absence of it.
The metabolic process by which energy is produced in the absence of O2 through the oxidation of organic compounds, typically sugars, to simpler organic compounds, such as pyruvate. Pyruvate is further processed to ethanol by alcoholic fermentation or lactic acid by lactate fermentation; see 'glycolysis'.
- Warburg effect
A term used to describe two unrelated observations in plant physiology and oncology, both from the work of Otto Warburg. In oncology, the Warburg effect refers to the high rate of glycolysis and lactate fermentation in the cytosol exhibited by most cancer cells, relative to the comparatively low rate of glycolysis and oxidation of pyruvate in mitochondria exhibited by most normal cells. In plant physiology, the Warburg effect is the inhibition of photosynthetic CO2 fixation by high concentrations of O2.
A quasi-independent postdoctoral appointment that is required for further academic advancement in German-speaking countries.
- Citric acid cycle
A cyclic series of eight enzymatic reactions that occur in the mitochondrial matrix and that convert acetyl CoA derived from carbohydrates, fatty acids and amino acids to CO2 and H2O; also known as the tricarboxylic acid (TCA) cycle or Krebs cycle.
- Aerobic glycolysis
The enzymatic transformation of glucose to pyruvate in the presence of O2; see 'glycolysis'.
- Oxidative phosphorylation
(OXPHOS). A metabolic process that occurs in mitochondria. It produces energy in the form of ATP from ADP and inorganic phosphate, and is driven by a proton gradient generated by the reactions of the citric acid cycle.
The situation in which the many hundreds of mitochondria within a single eukaryotic cell are a mixture of those that contain mutant mitochondrial DNA (mtDNA) and normal mtDNA. Heteroplasmy has a role in the severity of mitochondrial diseases.
The situation in which a mutation in mitochondrial DNA is present in all of the mitochondria within a single eukaryotic cell.
- Anaerobic glycolysis
The enzymatic transformation of glucose to pyruvate in the absence of O2; see 'glycolysis'.
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Koppenol, W., Bounds, P. & Dang, C. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11, 325–337 (2011). https://doi.org/10.1038/nrc3038
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