Gluconeogenesis in Cancer: Function and Regulation of PEPCK, FBPase, and G6Pase

Cancer cells display a high rate of glycolysis in the presence of oxygen to promote proliferation. Gluconeogenesis, the reverse pathway of glycolysis, can antagonize aerobic glycolysis in cancer via three key enzymes - phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase). Recent studies have revealed that, in addition to metabolic regulation, these enzymes also play a role in signaling, proliferation, and the cancer stem cell (CSC) tumor phenotype. Multifaceted regulation of PEPCK, FBPase, and G6Pase through transcription, epigenetics, post-translational modification, and enzymatic activity is observed in different cancers. We review here the function and regulation of key gluconeogenic enzymes and new therapeutic opportunities.