Rewiring of glycolysis in cancer cell metabolism.

Altered metabolism constitutes a nearly universal feature of cancer cells. This metabolic reorganization in part originates from the high proliferative state displayed by cancer cells. The nature of this altered metabolism is complex with multiple strategies implemented across diverse contextual dependencies to enable the accumulation of the biomass that is necessary for proliferation in a stressful tumor microenvironment. Proliferating cancer cells have differential requirements for the synthesis of nucleic acid, protein and lipid constituents. Regulation of cellular redox status is another essential metabolic need that must be accommodated in transformed cells. This may lead to an alteration of glucose metabolism that allows for the diversion of glycolytic flux into biosynthetic pathways such as the pentose phosphate pathway. Such a rewiring may also indirectly interact with mitochondrial tricarboxylic acid cycle (TCA) flux to allow for enhanced biosynthesis and generation of reducing equivalents from TCA cycle intermediates. However, in order to direct the movement of the appropriate carbon skeletons into the necessary anabolic and oxidative stress-protective pathways, changes in cofactor availability that define cellular redox state and energy status for metabolic enzymes are required. These cofactors include those that couple electron transfer during cellular redox reactions (such as NADH and NADPH) as well as nucleotides that regulate energy status and other functions such as ATP and GTP. It is often assumed that cancer cell metabolism may be adapted to meet high Rewiring of glycolysis in cancer cell metabolism