Hardonnière Kévin, Huc Laurence, Podechard Normand, Fernier Morgane, Tekpli Xavier, Gallais Isabelle, Sergent Odile, Lagadic-Gossmann Dominique
UMR Inserm 1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
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.
Toxicol In Vitro. 2015 Oct;29(7):1597-608. doi: 10.1016/j.tiv.2015.06.010. Epub 2015 Jun 15.
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.
苯并[a]芘（B[a]P）是多环芳烃的原型分子，具有基因毒性和致癌作用，这使得国际癌症研究机构将其认定为人类致癌物。除了由B[a]P触发的众所周知的凋亡信号外，也有研究表明存在存活信号，这两种信号可能都与癌症的发展有关。我们之前的研究表明，B[a]P可诱导大鼠肝上皮F258细胞的线粒体膜电位（ΔΨm）超极化。升高的ΔΨm在肿瘤的发生和发展中起作用，并且有人认为一氧化氮（NO）是导致ΔΨm升高的原因。因此，本研究旨在评估B[a]P对F258细胞中NO水平的影响，并测试NO作为存活信号的假定作用，特别是与ΔΨm的关系。我们的数据表明，暴露于B[a]P会导致NO的产生，这取决于诱导型NO合酶的激活。这种酶的激活涉及芳烃受体（AhR），可能还涉及p53的激活。阻止NO的产生不仅会增加B[a]P诱导的细胞死亡，还会阻止线粒体超极化。因此，这表明NO在暴露于B[a]P时作为存活信号发挥作用，可能靶向ΔΨm。
