Oncogenic alterations of the cellular metabolism were long regarded as a secondary effect of cancer, precipitated by genetic changes. More recently, this perception has changed and the deregulation of cellular energetics is now included in the Hallmarks of Cancer since their second iteration in 2011. This understanding is corroborated by the fact that many cancer driver mutations are also implicated in cellular metabolism and an estimated two thirds of cancers have mutations in glycolytic genes.
The most well-known adaptation of cancer cell metabolism is the Warburg effect, or aerobic glycolysis. It is named after Otto Heinrich Warburg who observed in the 1920s the production of lactic acid in tumor cells under aerobic conditions. The Warburg effect describes the preference of tumors for fermentation of glucose to lactate even in the presence of sufficient amounts of oxygen. Pyruvate, the end product of glycolysis, is reduced to lactate instead of being transported into the mitochondria for oxidative phosphorylation through the citric acid cycle. Lactate is transported out of the cell and contributes to the acidification of the tumor microenvironment (TME).
Gain of function mutations in the isocitrate dehydrogenase in the cytosol (IDH1) and in mitochondria (IDH2) lead to reduction of the α-ketoglutarate (α-KG) - one of the citric acid cycle metabolites – to R-2-hydroxyglutarate (2-HG). This oncometabolite inhibits α-KG-dependent dioxygenases by decreasing the concentration of their obligate cofactor α-KG. The class of α-KG-dependent dioxygenases comprises various chromatin-modifying demethylases and methyl transferases. Their inhibition leads to CpG island hypermethylation and affects cell fate. α-KG-dependent dioxygenases also include prolyl hydroxylases, which influence activity of the hypoxia-inducible factor 1 (HIF1), a master regulator of transcription in the adaptive response to hypoxia.
Regulation of transcription factors like HIF1 and Myc and activation of signaling pathways like PI3K/AKT signaling have been shown to contribute to the Warburg phenotype in cancer. Inactivation of tumor suppressors like p53 is also an important mechanism. Under normal conditions, p53 negatively regulates glycolysis and promotes oxidative phosphorylation. However, these mechanisms fail under aerobic glycolysis conditions, thus supporting continuous growth and survival of cancer cells.
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