Glycolysis breaks down glucose in the cytoplasm to generate pyruvate. In the absence of oxygen, pyruvate is reduced to lactate. In the presence of oxygen, pyruvate is oxidized by PDH to acetyl-CoA, which enters the mitochondria and the TCA cycle. Oxidative phosphorylation generates ATP as an energy source and also produces ROS. ROS can cause mitochondrial damage and apoptosis, both by stimulating the release of apoptotic factors and through activation of Kv1.5 channels.
Glycolytic metabolism can be promoted by oncogenic changes. For instance, the tumor suppressor p53 inhibits glycolysis through TIGAR induction and stimulates oxidative phosphorylation through SCO2 induction. In cancer cells with mutated p53, ROS-induced apoptosis is thus decreased. The oncogene DJ-1 also blocks ROS-induced apoptosis and may increase glycolysis by inhibiting PTEN and thereby activating PI-3 kinase and PKB. Hypoxia can induce glycolysis in cancer cells through HIF-1α stabilization and activation, and thereby the up-regulation of glycolytic enzymes.
Furthermore, hypoxia suppresses oxidative phosphorylation through the transcriptional activation of the gene encoding PDK. By inhibiting PDK, DCA may shift cancer cell metabolism back toward oxidative phosphorylation. Some cancer cells may use nonglucose energy sources such as amino acids, fatty acids, or nucleic acids. Wild-type p53 and DCA shift cancer cells toward oxidative phosphorylation and apoptosis. Oncogenic changes and hypoxia shift cancer cells toward glycolytic metabolism and survival. (source: sciencemag.org)