Warburg effect

high-resolution terminology - matching measurements at high-resolution

Warburg effect

Description

Recently, controversies had a renaissance on the much neglected Crabtree effect (aerobic glycolysis in a large range of cells exposed to glucose or fructose, with fully functional mitochondria; Crabtree 1929; Gnaiger and Kemp 1990) versus the Warburg effect (loss of mitochondrial function inducing cancer and stimulating compensatory aerobic glycolysis in the presence of oxygen; Warburg 1956; see list of references for reviews). Today it is widely accepted that ‘the Warburg effect is not consistent across all cancer types’ (Potter et al 2016) and reprogramming of mitochondrial energy metabolism represents a functional adjustment of cancer cells (Schöpf et al 2020).

Reference: Schoepf 2020 Nat Commun

Contributed by Gnaiger Erich 2020-03-25

Oxygen and pH - Warburg versus Crabtree Effect

Q: For quantification of aerobic glycolysis in intact cells, the measurement of proton production can be used as an indirect but continuous record of lactate production and corresponding acidification of the medium, while simultaneously monitoring oxygen concentration and oxygen consumption (MultiSensor-O2k). Is this related to the Warburg or Crabtree effect?

A: Under various metabolic conditions, lactic acid production is the dominant mechanism causing acidification, hence the pH measurement is a good indirect indicator of aerobic glycolysis. An early paper summarizing the literature in this field states:

"At high fructose concen­trations, respiration is inhibited while glycolytic end products accumulate, a phenomenon known as the Crabtree effect. It is commonly believed that this effect is restric­ted to microbial and tumour cells with uniquely high glycolytic capaci­ties (Sussman et al, 1980). How­ever, inhibition of respiration and increase of lactate production are observed under aerobic condi­tions in beating rat heart cell cultures (Frelin et al, 1974) and in isolated rat lung cells (Ayuso-Parrilla et al, 1978). Thus, the same general mechanisms respon­sible for the integra­tion of respiration and glycolysis in tumour cells (Sussman et al, 1980) appear to be operating to some extent in several isolated mammalian cells." Gnaiger 1990 Biochim Biophys Acta

References

• Burns JS, Manda G (2017) Metabolic pathways of the Warburg effect in health and disease: perspectives of choice, chain or chance. Int J Mol Sci 19;18:2755. doi: 10.3390/ijms18122755. PMID: 29257069

• Comito Giuseppina, Ippolito Luigi, Chiarugi Paola, Cirri Paolo (2020) Nutritional exchanges within tumor microenvironment: impact for cancer aggressiveness. Front Oncol 24 March 2020. - Open Access

• Crabtree HG (1929) Observations on the carbohydrate metabolism of tumours. Biochem J 23:536–45.

• DeBerardinis Ralph J, Chandel Navdeep S (2020) We need to talk about the Warburg effect. Nature Metabolism 2:127–9.

• Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak TW, Wang X (2010) The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143:711-24.

Warburg effect: "elevation of aerobic glycolysis seen in tumor cells"; "elevated lactate production under aerobic conditions".

• Ferreira LM (2010) Cancer metabolism: the Warburg effect today. Exp Mol Pathol 89:372-80. [PMID: 20804748]

• Gnaiger E, Kemp RB (1990) Anaerobic metabolism in aerobic mammalian cells: information from the ratio of calorimetric heat flux and respirometric oxygen flux. Biochim Biophys Acta 1016:328-32. - »Bioblast link«

• Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66:8927-30.

• Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–8. [PubMed: 26778478]

• Potter M, Newport E, Morten KJ (2016) The Warburg effect: 80 years on. Biochem Soc Trans 44:1499–505.

• Schöpf Bernd, Weissensteiner Hansi, Schäfer Georg, Fazzini Federica, Charoentong Pornpimol, Naschberger Andreas, Rupp Bernhard, Fendt Liane, Bukur Valesca, Giese Irina, Sorn Patrick, Sant’Anna-Silva Ana Carolina, Iglesias-Gonzalez Javier, Sahin Ugur, Kronenberg Florian, Gnaiger Erich, Klocker Helmut (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat Commun 2020-03-20 [Epub ahead of print]. - »Bioblast link«

• van Beek JHGM (2010) Computational model predictions of metabolic fluxes connecting cytosol and mitochondrial matrix under ‘Warburg effect’ conditions. Mitochondr Physiol Network 15.06:80.

• Vaupel P, Mayer A (2010) Evidence against a mitochondrial dysfunction in cancer cells as a hallmark of malignant growth. Mitochondr Physiol Network 15.06:79.

• Van der Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029-33.

• Warburg O (1956) On the origin of cancer cells. Science 123:309–14.

• Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269-70.

• Gentric G, Mieulet V, Mechta-Grigoriou F (2017) Heterogeneity in cancer metabolism: new concepts in an old field. Antioxid Redox Signal 26:462–85. - http://online.liebertpub.com/doi/full/10.1089/ars.2016.6750
• Xing Yazhi, Zhao Shimin, Zhou Binhua P, Mi Jun (2015) Metabolic reprogramming of the tumour microenvironment. FEBS J 282:3892–8. - http://onlinelibrary.wiley.com/doi/10.1111/febs.13402/full

MitoPedia methods: Respirometry