Mammalian Target Of Rapamycin Up-regulation Of PKM2 Is Critical For Aerobic Glycolysis And Tumor Growth

Under normxia condition, normal cells metabolize glucose using oxidative phosphorylation to generate ATP, whereas cancer cells primarily utilize aerobic glycolysis to consume glucose and produce large amount of lactate. Since aerobic glycolysis of cancer cells was first discovered by German Nobel laureate Otto Warburg during 1920s, this characteristic metabolism in cancer cells is also called Warburg effect. However, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear.Pyruvate kinase (PK) is a key rate-limiting glycolytic enzyme, which catalyzes the phosphoenolpyruvate (PEP) to pyruvate. The isoenzyme of PK is one of the frequently altered glycolytic enzymes in cancer cells. There are four isoenzymes of PK, each is expressed in different tissues. For a largely unknown regulatory mechanism, the pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and especially tumor cells, and plays an essential role in tumor metabolism and growth.The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a highly conserved pathway that plays important roles in the regulation of cell survival, proliferation, stress and metabolism. The mutations of both proto-oncogenes such as RTKs, PI3K, AKT, and tumor suppressor genes such as PTEN and TSC1/TSC2 in the upstream of the mTOR pathway made it one of the most frequently dysregulated signaling pathway in human diseases, especially in cancers. However, the precise mechanisms about how hyperactivated mTOR signaling leading to tumorigenesis is not well elucidated. Here, we explored its potential role in cancer metabolism.We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. The augmented aerobic glycolysis was exsited in malignant tumorigenic Pten-/- MEF cell lines, benign tumorigenic Tsc1-and Tsc2-null MEF cell lines, and even senescent primary Tsc1-/- or Tsc2-/- MEFs. PKM2 level was augmented in mouse kidney tumors due to deficiency of TSC2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia- inducible factor1α(HIF1α)-mediated transcription activation, and c-Myc-heterogenous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells.Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1α/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.