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J. Biol. Chem., Vol. 281, Issue 14, 9093-9100, April 7, 2006

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Effects of Polycyclic Aromatic Hydrocarbons (PAHs) on Vascular Endothelial Growth Factor Induction through Phosphatidylinositol 3-Kinase/AP-1-dependent, HIF-1-independent Pathway^*

Jin Ding¹, Jingxia Li¹, Jingyuan Chen¹, Haobin Chen, Weiming Ouyang, Ronghe Zhang, Caifang Xue, Dongyun Zhang, Shantu Amin^¶, Dhimant Desai^¶, and Chuanshu Huang²

From the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, the Department of Etiology and Department of Occupational and Environmental Health Sciences, Fourth Military Medical University, 17 Changlexi Road, Xi'an, Shaanxi 710032, China, and the ^¶Department of Pharmacology, School of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17033

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-1 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 p85 (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-1-independent pathways. These findings may help us to understand the mechanisms involved in PAH carcinogenic effects.

Received for publication, September 26, 2005 , and in revised form, January 11, 2006.

^* This work was supported in part by Grants CA112557, CA103180, and CA094964 from the NCI, National Institutes of Health and Grants ES012451, ES000260, and ES010344 from the NIEHS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Nelson Inst. of Environmental Medicine, NY University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987. Tel.: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

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