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.

Plant 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.

Basis
In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. The latter process is aerobic (uses oxygen). Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.

Otto Warburg postulated that this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis. Today it is known that mutations in oncogenes and tumor suppressor genes are responsible for malignant transformation however a fundamental cause of cancer - if there is any - is still not understood.

Use in diagnosis
The Warburg effect has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2-18F-2-deoxyglucose (FDG) (a radioactive modified hexokinase substrate) with positron emission tomography (PET).

Possible explanations of the effect
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. It may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, it has been proposed that cancer cells (and normal proliferating cells) may need to activate glycolysis despite the presence of oxygen in order to proliferate. There is also evidence that attributes some of the high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase responsible for driving the high glycolytic activity.

Tumor M2-PK, an enzyme thought to be responsible for the effect
In March 2008 Lewis C. Cantley and colleagues at the Harvard Medical School announced that they had identified the enzyme that gave rise to the Warburg Effect. The researchers stated that Tumor M2-PK, a form of the pyruvate kinase enzyme, is produced in all rapidly-dividing cells and is responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of Tumor M2-PK, their growth was curbed. 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.

Glycolytic Inhibitors
Many substances have been developed which inhibit glycolysis, and such glycolytic inhibitors are currently the subject of intense research as anticancer agents. Some glycolytic inhibitors currently being studied as anticancer treatments include SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, Bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid (DCA). Clinical trials are ongoing for 2-DG and DCA ClinicalTrials.gov.

DCA, a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, downregulates glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA might have therapeutic benefits against many types of cancers.

Alternative models
A model called the Reverse Warburg Effect in which the cells producing energy by glycolysis were not the tumor cells, but the stromal fibroblasts. Although it was stated that the Warburg Effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.