title: Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.
abstract: Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, 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. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1α (HIF1α)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 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.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.forename: Xinxin
authors.initials: X
authors.lastname: Chen
authors.forename: Jianhui
authors.initials: J
authors.lastname: Ma
authors.forename: Haiyong
authors.initials: H
authors.lastname: Peng
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Jing
authors.forename: Hongwang
authors.initials: H
authors.lastname: Yang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Chen
authors.forename: Long
authors.initials: L
authors.lastname: Chang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: June
authors.initials: J
authors.lastname: Goto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Onda
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
authors.forename: Han
authors.initials: H
authors.lastname: You
authors.forename: David
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000332:Aerobiosis; D000818:Animals; D049109:Cell Proliferation; D016259:Genes, myc; D006019:Glycolysis; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011770:Pyruvate Kinase / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C546842:MTOR protein, human; C546843:mTOR protein, mouse; D011770:Pyruvate Kinase; D058570:TOR Serine-Threonine Kinases