Journal Article

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

Jingyuan Chen, Yan Yan, Jingxia Li, Qian Ma, Gary D. Stoner, Jianping Ye and Chuanshu Huang

in Carcinogenesis

Volume 26, issue 6, pages 1035-1043
Published in print June 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi052
Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells

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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-κB (NFκB) activation by either NEMO-BDBP, an NFκB specific inhibitor, or overexpression of DN-IκBα or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NFκB 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.

Keywords: B[a]P, benzo[a]pyrene; B[a]PDE, (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide; CDE, chrysene-1,2-diol-3,4-epoxide; DMSO, dimethyl sulfoxide; ERKs, extracellular signal-regulated protein kinases; FBS, fetal bovine serum; IκBα, inhibitory subunit kappa-B; IKKβ, IκB kinase β; iNOS, inducible nitric oxide synthase; JNKs, c-Jun N-terminal kinases; 5-MCDE, (±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide; MAPKs, mitogen-activated protein kinases; NFκB, nuclear factor-κB; PAHs, polycyclic aromatic hydrocarbons.

Journal Article.  6576 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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