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Carcinogenesis Advance Access originally published online on February 17, 2005
Carcinogenesis 2005 26(6):1035-1043; doi:10.1093/carcin/bgi052
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Carcinogenesis vol.26 no.6 © Oxford University Press 2005; all rights reserved.

Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells

Jingyuan Chen 1, 2, {dagger}, Yan Yan 1, 2, {dagger}, Jingxia Li 1, {dagger}, Qian Ma 1, Gary D. Stoner 3, Jianping Ye 4 and Chuanshu Huang 1, *

1 Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA, 2 Department of Occupational and Environmental Health Sciences, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China, 3 Division of Environmental Health Sciences, School of Public Health, The Ohio State University, Columbus, OH 43210, USA and 4 Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA

* To whom correspondence should be addressed. Tel: +1 845 731 3519; Fax: +1 845 351 2118; Email: chuanshu{at}env.med.nyu.edu

Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. Furthermore, impairing nuclear factor-{kappa}B (NF{kappa}B) activation by either NEMO-BDBP, an NF{kappa}B specific inhibitor, or overexpression of DN-I{kappa}B{alpha} or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NF{kappa}B pathway is also required for the induction of iNOS by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or c-JunN-terminal kinase inhibitor II, resulted in an increased induction of iNOS. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on the expression of iNOS. These results suggest that B[a]P initiates the signaling pathways leading to the induction of iNOS in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal SCC in humans, we speculate that the induction of iNOS by B[a]P may be one mechanism by which B[a]P could produce carcinogenic effects in the human esophagus.


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