Warburg effect

The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.

Physiology

In plant physiology, the Warburg effect is the inhibition of carbon dioxide fixation, and subsequently of photosynthesis, by high oxygen concentrations. The oxygenase activity of RuBisCO, which initiates the process of photorespiration, largely accounts for this effect.

Oncology

Basis

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by glycolysis followed by lactic acid fermentation in the cytosol, rather than by oxidation of pyruvate in mitochondria like most normal cells. [cite journal |author=Kim JW, Dang CV |title=Cancer's molecular sweet tooth and the Warburg effect |journal=Cancer Res. |volume=66 |issue=18 |pages=8927–30 |year=2006 |pmid=16982728 |doi=10.1158/0008-5472.CAN-06-1501 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16982728] This occurs even if oxygen is plentiful. Otto Warburg postulated that this change in metabolism is the fundamental cause of cancer,cite journal | author = Warburg O | title = On the origin of cancer cells | journal = Science | volume = 123 | issue = 3191 | pages = 309–14 | year = 1956 | pmid = 13298683 | doi = 10.1126/science.123.3191.309 | issn = ] a claim now known as the Warburg hypothesis. Today it is known that mutations in oncogenes and tumor suppressor genes are the fundamental cause of cancer. [cite journal |author=Bertram JS |title=The molecular biology of cancer |journal=Mol. Aspects Med. |volume=21 |issue=6 |pages=167–223 |year=2000 |pmid=11173079 |doi=10.1016/S0098-2997(00)00007-8] [cite journal |author=Grandér D |title=How do mutated oncogenes and tumor suppressor genes cause cancer? |journal=Med. Oncol. |volume=15 |issue=1 |pages=20–6 |year=1998 |pmid=9643526 |doi=10.1007/BF02787340] The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria because they are involved in the cell's apoptosis program which would otherwise kill cancerous cells.

Role in cancer

On 16 March 2008 it was reported that Harvard Medical School announced that they had identified the enzyme that gave rise to the Warburg Effect.cite journal | author = Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC | title = The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth | journal = Nature | volume = 452 | issue = 7184 | pages = 230–3 | year = 2008 | pmid = 18337823 | doi = 10.1038/nature06734 | issn = ] [cite journal |author=Pedersen PL |title=Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen |journal=J. Bioenerg. Biomembr. |volume=39 |issue=3 |pages=211–22 |year=2007 |pmid=17879147 |doi=10.1007/s10863-007-9094-x]

HMS researchers stated that pyruvate kinase M2, an enzyme variety produced in all rapidly-dividing cells, was responsible for enabling cancer cells to consume glucose at an accelerated rate, and on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of Tumor M2-PK, their growth was curbed. They also demonstrated that on introducing the cells to laboratory mice, their ability to devlope tumours was severely compromised. The researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across different forms of cancer, however PKM2 was identified in all of the cancer cells they had experimented upon. The enzyme variety is not usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g. in healing wounds or hematopoiesis.

The use of dichloroacetic acid for cancer treatment using this methodology was published by researchers at the University of Alberta in January 2007.cite journal | author = Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED | title = A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth | journal = Cancer Cell | volume = 11 | issue = 1 | pages = 37–51 | year = 2007 | pmid = 17222789 | doi = 10.1016/j.ccr.2006.10.020 | issn = ] cite journal | author = Pan JG, Mak TW | title = Metabolic targeting as an anticancer strategy: dawn of a new era? | journal = Sci. STKE | volume = 2007 | issue = 381 | pages = pe14 | year = 2007 | pmid = 17426345 | doi = 10.1126/stke.3812007pe14 | issn = ] Trials are continuingcite journal | author = Pearson H | title = Cancer patients opt for unapproved drug | journal = Nature | volume = 446 | issue = 7135 | pages = 474–5 | year = 2007 | pmid = 17392750 | doi = 10.1038/446474a | issn = ] , but the drug is known to exhibit significant neurotoxic and hepatotoxic effects and even if effective the side effects (contrary to mass media reports) may be prohibitive for most patients. Ironically, prolonged medication with DCA might be a way to kill off most tumors, at the cost of a much-increased risk of developing liver cancer.

References