Abstract

We elucidated instrumental mechanisms of the Warburg effect, discovered the protein kinase and phosphatase activity of metabolic enzymes, and revealed the non-metabolic functions of metabolic enzymes in tumorigenesis. (1) Our work elucidated important mechanisms underlying the RTK-promoted Warburg effect, which are regulated by nuclear function of pyruvate kinase M2 (PKM2) and mitochondrial function of phosphoglycerate kinase 1 (PGK1). RTK activation induces translocation of the glycolytic enzyme PKM2 into the nucleus, where it binds to and activates tyrosine-phosphorylated β-catenin, thereby upregulating expression of glycolytic genes and enhancing the glucose uptake and lactate production. In addition, we revealed that activation of RTKs, expression of K-Ras G12V and B-Raf V600E, and hypoxia induce the mitochondrial translocation of the glycolytic enzyme PGK1, which phosphorylates and activates pyruvate dehydrogenase kinase 1 (PDHK1) to inhibit mitochondrial pyruvate metabolism, thereby promoting the Warburg effect. (2) We discovered that metabolic enzymes (PKM2, PGK1, PCK1, HK2, and fructokinase KHK-A) can function as protein kinases to regulates cell cycle progression, mitochondrial function, autophagy, and de novo nucleic acid synthesis. (3) We discovered for the first time that metabolic enzymes can function as protein phosphatase. Fructose-1,6-bisphosphatase 1 (FBP1) dephosphorylates histone H3 at T11 and suppresses gene transcription. (4) Our work revealed that metabolic enzymes, including fumarase, acetyl-CoA synthetase 2 (ACSS2), and α-ketoglutarate dehydrogenase (KGDH) can possess nonmetabolic functions in regulation of instrumental cellular activities including DNA repair and gene expression. The discoverers of tumor-promoting functions of metabolic enzymes provide novel approaches for diagnosis and treatment of human cancer.