title: Glucose metabolism and hexosamine pathway regulate oncogene-induced senescence.
abstract: Oncogenic stress-induced senescence (OIS) prevents the ability of oncogenic signals to induce tumorigenesis. It is now largely admitted that the mitogenic effect of oncogenes requires metabolic adaptations to respond to new energetic and bio constituent needs. Yet, whether glucose metabolism affects OIS response is largely unknown. This is largely because of the fact that most of the OIS cellular models are cultivated in glucose excess. In this study, we used human epithelial cells, cultivated without glucose excess, to study alteration and functional role of glucose metabolism during OIS. We report a slowdown of glucose uptake and metabolism during OIS. Increasing glucose metabolism by expressing hexokinase2 (HK2), which converts glucose to glucose-6-phosphate (G6P), favors escape from OIS. Inversely, expressing a glucose-6-phosphatase, [corrected] pharmacological inhibition of HK2, or adding nonmetabolizable glucose induced a premature senescence. Manipulations of various metabolites covering G6P downstream pathways (hexosamine, glycolysis, and pentose phosphate pathways) suggest an unexpected role of the hexosamine pathway in controlling OIS. Altogether, our results show that decreased glucose metabolism occurs during and participates to OIS.
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Gitenay
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Wiel
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: H
authors.initials: H
authors.lastname: Lallet-Daher
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: 1] Institut de Pathologie, CHRU, Faculté de Médecine, Université de Lille, Lille, France [2] Inserm U837, Jean-Pierre Aubert Research Center, Team 5, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Aubert
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France [5] Biochemistry Laboratory of Lyon Sud, Hospices civils de Lyon, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Payen
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: H
authors.initials: H
authors.lastname: Simonnet
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Bernard
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009857:Oncogenes; D010427:Pentose Phosphate Pathway; D013997:Time Factors; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D006595:Hexosamines; D019298:Glucose-6-Phosphate; D006593:Hexokinase; D005947:Glucose