Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

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.

[1]  L. Cantley,et al.  Cancer Cell Metabolism , 2012 .

[2]  S. Mazurek.  Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. , 2011, The international journal of biochemistry & cell biology.

[3]  I. Harris,et al.  Cancer cell metabolism. , 2011, Cold Spring Harbor symposia on quantitative biology.

[4]  M. Ohh,et al.  Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. , 2010, Cancer letters.

[5]  S. Dry,et al.  PTEN loss accelerates KrasG12D-induced pancreatic cancer development. , 2010, Cancer research.

[6]  Jason W. Locasale,et al.  Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells , 2010, Science.

[7]  Steven P Gygi,et al.  Akt–RSK–S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases , 2010, Science Signaling.

[8]  Qicheng Ma,et al.  Activation of a metabolic gene regulatory network downstream of mTOR complex 1. , 2010, Molecular cell.

[9]  Sang Gyun Kim,et al.  Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. , 2010, Molecular cell.

[10]  K. Podar,et al.  A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. , 2010, Cell cycle.

[11]  Shikha Khatri,et al.  FOXO3a Regulates Glycolysis via Transcriptional Control of Tumor Suppressor TSC1* , 2010, The Journal of Biological Chemistry.

[12]  M. Pollak,et al.  Loss of function of PTEN alters the relationship between glucose concentration and cell proliferation, increases glycolysis, and sensitizes cells to 2-deoxyglucose. , 2010, Cancer letters.

[13]  G. Semenza.  HIF-1: upstream and downstream of cancer metabolism. , 2010, Current opinion in genetics & development.

[14]  M. Assanah,et al.  HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer , 2010, Nature.

[15]  A. Krainer,et al.  The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism , 2010, Proceedings of the National Academy of Sciences.

[16]  Ying Wang,et al.  Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. , 2010, The Journal of clinical investigation.

[17]  David M Sabatini,et al.  mTOR and cancer: many loops in one pathway. , 2009, Current opinion in cell biology.

[18]  David M. Sabatini,et al.  An Emerging Role of mTOR in Lipid Biosynthesis , 2009, Current Biology.

[19]  L. Huang,et al.  An Essential Role of the HIF‐1α–c‐Myc Axis in Malignant Progression , 2009, Annals of the New York Academy of Sciences.

[20]  Maria C. Mitterberger,et al.  Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply. , 2009, Experimental cell research.

[21]  K. Kinzler,et al.  Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells , 2009, Science.

[22]  D. Kwiatkowski,et al.  A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles. , 2009, Human molecular genetics.

[23]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[24]  M. Ohh,et al.  Differential Dependence of Hypoxia-inducible Factors 1α and 2α on mTORC1 and mTORC2* , 2008, Journal of Biological Chemistry.

[25]  T. Mak,et al.  The roles of PTEN in development, physiology and tumorigenesis in mouse models: a tissue-by-tissue survey , 2008, Oncogene.

[26]  R. Parsons,et al.  The role of PTEN signaling perturbations in cancer and in targeted therapy , 2008, Oncogene.

[27]  D. Sabatini,et al.  Cancer Cell Metabolism: Warburg and Beyond , 2008, Cell.

[28]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[29]  Ru Wei,et al.  The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth , 2008, Nature.

[30]  Ralph J Deberardinis,et al.  Brick by brick: metabolism and tumor cell growth. , 2008, Current opinion in genetics & development.

[31]  Vincent J Schmithorst,et al.  Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. , 2008, The New England journal of medicine.

[32]  Chi V. Dang,et al.  The interplay between MYC and HIF in cancer , 2008, Nature Reviews Cancer.

[33]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[34]  A. Tee,et al.  Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif* , 2007, Journal of Biological Chemistry.

[35]  G. Semenza,et al.  HIF-1 mediates the Warburg effect in clear cell renal carcinoma , 2007, Journal of bioenergetics and biomembranes.

[36]  T. Mak,et al.  Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era? , 2007, Science's STKE.

[37]  Annie P. Moseman,et al.  PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. , 2007, The Journal of clinical investigation.

[38]  R. Rodenburg,et al.  Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. , 2007, The Journal of clinical investigation.

[39]  Ming You,et al.  TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth , 2006, Cell.

[40]  S. Oldham,et al.  The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-α/Sima , 2005, Journal of Cell Science.

[41]  G. Semenza,et al.  Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways , 2005, Oncogene.

[42]  Jung Weon Lee,et al.  The FASEB Journal express article 10.1096/fj.04-3099fje. Published online May 26, 2005. ©2005 FASEB , 2022 .

[43]  R. Gillies,et al.  Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors , 2005 .

[44]  R. Gillies,et al.  Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. , 2005, Neoplasia.

[45]  J. Brugarolas,et al.  Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. , 2004, Cancer cell.

[46]  A. Alavi,et al.  Akt Stimulates Aerobic Glycolysis in Cancer Cells , 2004, Cancer Research.

[47]  Hongbing Zhang,et al.  Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. , 2003, The Journal of clinical investigation.

[48]  Hongbing Zhang,et al.  Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. , 2003, Cancer research.

[49]  William R Sellers,et al.  TSC2 regulates VEGF through mTOR-dependent and -independent pathways. , 2003, Cancer cell.

[50]  Hongbing Zhang,et al.  Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma , 2003, The Lancet.

[51]  Tian Xu,et al.  Akt regulates growth by directly phosphorylating Tsc2 , 2002, Nature Cell Biology.

[52]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[53]  J. Blenis,et al.  Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. , 2002, Molecular cell.

[54]  Hongbing Zhang,et al.  A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. , 2002, Human molecular genetics.

[55]  G. Semenza,et al.  Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. , 1994, The Journal of biological chemistry.

[56]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[57]  T. S. P. S.,et al.  GROWTH , 1924, Nature.