title: The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival.
abstract: Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na(+)/H(+) exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), F-35043 Rennes, France.|Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Hardonnière
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Saunier
authors.affiliation: Inserm-U1037, University of Toulouse, Cancer Research Center of Toulouse CRCT, Department of Experimental Therapeutics 2 av. Hubert Curien, 31100 Toulouse, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lemarié
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), F-35043 Rennes, France.|Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Fernier
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), F-35043 Rennes, France.|Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gallais
authors.affiliation: INRA UMR 1331 ToxAlim (Research Center in Food Toxicology), University of Toulouse ENVT, INP, UPS, 180 Chemin de Tournefeuille, F-31027, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Héliès-Toussaint
authors.affiliation: Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Université de Nice-Sophia Antipolis, Faculté de Médecine, Centre Antoine Lacassagne, Nice, F-06107, France.
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.
authors.forename: Samantha
authors.initials: S
authors.lastname: Antonio
authors.affiliation: Hôpital Robert Debré, INSERM UMR1141, Bâtiment Ecran, 48 Boulevard Sérurier, Paris 75019, France.|U.F.R. de Médecine Université Paris Diderot, Paris 75019, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: Hôpital Robert Debré, INSERM UMR1141, Bâtiment Ecran, 48 Boulevard Sérurier, Paris 75019, France.|U.F.R. de Médecine Université Paris Diderot, Paris 75019, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.|Biochimie Métabolique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Necker-Enfants Malades, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.|Biochimie Métabolique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Necker-Enfants Malades, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Habarou
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.|Biochimie Métabolique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Necker-Enfants Malades, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Lavault
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Benelli
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), F-35043 Rennes, France.|Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Sergent
authors.affiliation: INRA UMR 1331 ToxAlim (Research Center in Food Toxicology), University of Toulouse ENVT, INP, UPS, 180 Chemin de Tournefeuille, F-31027, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.affiliation: Inserm UMR 1124, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bortoli
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), F-35043 Rennes, France.|Université de Rennes 1, Structure fédérative de recherche Biosit, UMS CNRS 3480/US Inserm 018, F 35043 Rennes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival; D065150:Cellular Reprogramming / Q000187:drug effects*; D002952:Citric Acid Cycle / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D000074082:Sodium-Hydrogen Exchanger 1 / Q000378:metabolism*
chemical_list: D002274:Carcinogens, Environmental; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D019344:Lactic Acid; D001564:Benzo(a)pyrene