ToxSci Advance Access originally published online on April 30, 2008
Toxicological Sciences 2008 104(2):283-293; 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
* Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
School of Medical Technology and Biotechnology, Taipei Medical University, Taipei, Taiwan
1 To whom correspondence should be addressed at Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan 70428, Taiwan. Fax: +886-6-275-2484. E-mail: yjwang{at}mail.ncku.edu.tw.
Received December 30, 2007; accepted April 17, 2008
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Abstract |
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Cigarette smoke is a major risk factor for bladder cancer. The main component in cigarette smoke, nicotine, can be detected in the urine of smokers. Nicotine has been implicated as a cocarcinogen that promotes lung cancer development through prosurvival 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 extracellular signal regulated kinase 1/2 (ERK1/2) in T24 cells. Stat3 activation via nicotinic acetylcholine receptor (nAChR)/protein kinase C signaling pathway was closely linked to Stat3 induction and nuclear factor-
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.