title: AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.
abstract: AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.
authors.affiliation: Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Faubert
authors.forename: Gino
authors.initials: G
authors.lastname: Boily
authors.forename: Said
authors.initials: S
authors.lastname: Izreig
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.forename: Bozena
authors.initials: B
authors.lastname: Samborska
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.forename: Fanny
authors.initials: F
authors.lastname: Dupuy
authors.forename: Christopher
authors.initials: C
authors.lastname: Chambers
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fuerth
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Orval A
authors.initials: OA
authors.lastname: Mamer
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D006019:Glycolysis; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases