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Carcinogenesis Advance Access published online on February 17, 2005
Carcinogenesis, doi:10.1093/carcin/bgi052
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received November 4, 2004
Revised January 13, 2005
Accepted February 8, 2005

CANCER BIOLOGY

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

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

* To whom correspondence should be addressed.
Chuanshu Huang, E-mail: chuanshu{at}env.med.nyu.edu


  Abstract

Inducible nitric oxide synthase (iNOS) overexpression has been reported in several human cancers, including esophageal squamous cell carcinoma. 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 iNOS induction and on signaling pathways leading to iNOS 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 iNOS expression. The induction of iNOS by B[a]P was found to occur through 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 iNOS induction by B[a]P. Furthermore, impairing 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 B[a]P-induced iNOS expression, suggesting NF{kappa}B pathway is also required for iNOS induction by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or with JNK inhibitor II, resulted in increased iNOS induction. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on iNOS expression. These results suggest that B[a]P initiates signaling pathways leading to iNOS induction in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal squamous cell carcinoma in human, we speculate that iNOS induction by B[a]P may be one mechanism through which B[a]P could produce carcinogenic effects in the human esophagus.

Keywords: iNOS; NF{kappa}B; B[a]P; kinase; signal transduction pathway.
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