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ToxSci Advance Access published online on April 30, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn086
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Published by Oxford University Press 2008.

Rapid Activation of Stat3 and ERK1/2 by Nicotine Modulates Cell Proliferation in Human Bladder Cancer Cells

Rong-Jane Chen*, Yuan-Soon Ho{dagger}, How-Ran Guo* and Ying-Jan Wang*

* Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan {dagger} School of Medical Technology and Biotechnology, Taipei Medical University, Taipei, Taiwan

Address correspondence and reprint requests: Ying-Jan Wang PhD, Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan 70428, Taiwan, Tel: 886-6-235-3535 Ext. 5804, Fax: 886-6-275-2484 Email: yjwang{at}mail.ncku.edu.tw

Received December 30, 2007; revision received March 28, 2008; accepted April 17, 2008


  Abstract

Cigarette smoke is a major risk factor for bladder cancer. The main component in cigarette smoke, nicotine, can be detected in the urine of smoker's. Nicotine has been implicated as a co-carcinogen that promotes lung cancer development of through pro-survival pathways. Although the mechanisms of nicotine-induced cell proliferation have been well studied in lung epithelial cells, the molecular mechanism of its action in bladder epithelial cells is still unclear. The aims of this study were to investigate whether there is nicotine induced bladder epithelial cell proliferation and to identify the signaling transduction pathway regulated by nicotine. We found that nicotine simultaneously activates Stat3 and ERK1/2 in T24 cells. Stat3 activation via nAChR/PKC signaling pathway was closely linked to Stat3 induction and NF-{kappa}B DNA binding activity, which is associated with Cyclin D1 expression and cell proliferation. ERK1/2 activation through nAChR and β-adrenoceptors plays a dual role in cell proliferation; it phosphorylates Stat3 at Ser727 and regulates cell proliferation. We conclude that through nAChR and β-adrenoceptors, nicotine activates ERK1/2 and Stat3 signaling pathways, leading to Cyclin D1 expression and cell proliferation. This is the first study to investigate signaling effects of nicotine in bladder cells. The current findings suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development.

Key Words: nicotine; bladder cancer; nicotinic acetylcholine receptor; Stat3; ERK1/2.


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