Figure 2. The potential roles of PDKs in malignant tumors.

The metabolic form of glucose in cells is pyruvate. Most of the pyruvate in noncancer cells enters the mitochondria under aerobic conditions, and a small part is metabolized into lactic acid. PDH in the mitochondria converts pyruvate into acetyl-CoA, which enters the TCA cycle. In tumor cells, the oxidative (mitochondrial) pathway for glucose utilization is inhibited, and most of pyruvate is converted to lactic acid. PDK inhibited by DCA inhibits PDH phosphorylation and regulates its activity. Myc, Wnt, and hypoxia-inducible factors (HIFs) individually or cooperatively transcribe one or more pyruvate dehydrogenase kinases in cancer cells. HIF-1 induces PDK to inactivate PDH and inhibits TCA circulation and mitochondrial respiration. HIF-1 can also stimulate the expression of glycolysis and LDH, thereby promoting the conversion of pyruvate to lactic acid.