title: Effects of polycyclic aromatic hydrocarbons (PAHs) on vascular endothelial growth factor induction through phosphatidylinositol 3-kinase/AP-1-dependent, HIF-1alpha-independent pathway.
abstract: Previous studies have demonstrated that exposure to polycyclic aromatic hydrocarbons (PAHs) and its derivatives is associated with an increased risk of skin cancers, and the carcinogenic effect of PAHs is thought to involve both tumor initiation and promotion. Whereas PAH tumor initiation is well characterized, the mechanisms involved in the tumor promotion of PAHs remain elusive. In the present study, we investigated the effects of PAHs on vascular endothelial growth factor (VEGF) expression by comparison of its induction between the active metabolite and its parent compound (B[a]PDE versus B[a]P) or between active compound and its relatively inactive analog (5-MCDE versus CDE). We found that exposure of cells to (+/-)-anti-benzo-[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) or (+/-)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE) led to marked induction of VEGF in Cl41 cells, whereas benzo[a]pyrene (B[a]P) or chrysene-1,2-diol-3,4-epoxide (CDE) did not exhibit significant inductive effects. Exposure of cells to B[a]PDE and 5-MCDE did not induce HIF-1alpha activation, whereas AP-1 was significantly activated. Moreover, overexpression of TAM67 (a dominant-negative mutant c-Jun) dramatically blocked that VEGF induction. Electrophoretic mobility shift assay showed that AP-1 was only able to specifically recognize and bind to its AP-1 potential binding site within -1136 and -1115 of the VEGF promoter region. Site-directed mutation of this AP-1 binding site eliminated the VEGF transcriptional activity induced by B[a]PDE, suggesting that the AP-1 binding site between -1136 and -1115 in the VEGF promoter region is critical for VEGF induction by B[a]PDE. In addition, overexpression of Deltap85 (a dominant-negative mutant PI-3K) impaired B[a]PDE- and 5-MCDE-induced VEGF induction. Considering our previous findings that PI-3K is an upstream mediator for c-Jun/AP-1 activation, we conclude that the VEGF induction by B[a]PDE and 5-MCDE is through PI-3K/AP-1-dependent and HIF-1alpha-independent pathways. These findings may help us to understand the mechanisms involved in PAH carcinogenic effects.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
authors.forename: Haobin
authors.initials: H
authors.lastname: Chen
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Ronghe
authors.initials: R
authors.lastname: Zhang
authors.forename: Caifang
authors.initials: C
authors.lastname: Xue
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D000078404:Epidermal Cells; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology* / Q000633:toxicity*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000503:physiopathology; D018808:Transcription Factor AP-1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011084:Polycyclic Aromatic Hydrocarbons; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases