title: Benzo[a]pyrene-induced nitric oxide production acts as a survival signal targeting mitochondrial membrane potential.
abstract: Benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, which has led the International Agency for Research on Cancer to recognize it as a human carcinogen. Besides the well-known apoptotic signals triggered by B[a]P, survival signals have also been suggested to occur, both signals likely involved in cancer promotion. Our previous work showed that B[a]P induced an hyperpolarization of mitochondrial membrane potential (ΔΨm) in rat hepatic epithelial F258 cells. Elevated ΔΨm plays a role in tumor development and progression, and nitric oxide (NO) has been suggested to be responsible for increases in ΔΨm. The present study therefore aimed at evaluating the impact of B[a]P on NO level in F258 cells, and at testing the putative role for NO as a survival signal, notably in link with ΔΨm. Our data demonstrated that B[a]P exposure resulted in an NO production which was dependent upon the activation of the inducible NO synthase. This enzyme activation involved AhR and possibly p53 activation. Preventing NO production not only increased B[a]P-induced cell death but also blocked mitochondrial hyperpolarization. This therefore points to a role for NO as a survival signal upon B[a]P exposure, possibly targeting ΔΨm.
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Hardonnière
authors.affiliation: INRA, ToxAlim (Research Centre in Food Toxicology), 180 chemin de Tournefeuille, BP 93173, F-31027 Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, 31027 Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
authors.forename: Normand
authors.initials: N
authors.lastname: Podechard
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Fernier
authors.affiliation: Stem Cell Group, Nordic EMBL PartnershipCentre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway.
authors.forename: Xavier
authors.initials: X
authors.lastname: Tekpli
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gallais
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Sergent
authors.affiliation: UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France. Electronic address: dominique.lagadic@univ-rennes1.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002273:Carcinogens; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D001564:Benzo(a)pyrene; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: AhR; Apoptosis; Benzo[a]pyrene; Mitochondrial membrane hyperpolarization; Nitric oxide; Survival