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ToxSci Advance Access originally published online on September 26, 2006
Toxicological Sciences 2007 96(1):21-29; doi:10.1093/toxsci/kfl118
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional Role of ß-Adrenergic Receptors in the Mitogenic Action of Nicotine on Gastric Cancer Cells

Vivian Yvonne Shin*, William Ka Kei Wu*, Kent Man Chu{dagger}, Marcel Wing Leung Koo*, Helen Pui Shan Wong*, Emily Kai Yee Lam*, Emily Kin Ki Tai* and Chi Hin Cho*,{ddagger},1

* Department of Pharmacology {dagger} Department of Surgery {ddagger} Research Centre of Infection and Immunology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China

1 To whom correspondence should be addressed at Department of Pharmacology, Faculty of Medicine Building, 21 Sassoon Road, The University of Hong Kong, Hong Kong, HKSAR, China. Fax: +852-2817-0859. E-mail: chcho{at}hkusua.hku.hk.

Received July 12, 2006; accepted September 13, 2006


  Abstract

We previously reported that nicotine promoted gastric cancer cell growth via upregulation of cyclooxygenase 2 (COX-2). In the present study, we further investigated whether ß-adrenoceptors, protein kinase C (PKC), and extracellular signal–regulated kinase-1/2 (ERK1/2) were involved in the modulation of COX-2 expression and cell proliferation by nicotine in AGS, a human gastric adenocarcinoma cell line. Results showed that nicotine dose dependently increased the phosphorylation of EKR1/2 and the expression of AP-1 subunits c-fos and c-jun. In this connection, the ERK1/2 inhibitor U0126 abrogated the upregulation of AP-1 and COX-2 as well as cell proliferation induced by nicotine. Moreover, nicotine induced the translocation of PKC-ßI from cytosol to membrane and increased the total levels of PKC expression. Inhibition of PKC by staurosporine attenuated nicotine-induced ERK1/2 phosphorylation and COX-2 expression. Furthermore, atenolol and ICI 118,551, a ß1- and ß2-adrenoceptor antagonist, respectively, reversed the stimulatory action of nicotine on the expression of PKC, ERK1/2 phosphorylation, and COX-2 together with cell proliferation. Collectively, these results suggest that nicotine stimulates gastric cancer cell growth through the activation of ß-adrenoceptors and the downstream PKC-ßI/ERK1/2/COX-2 pathway.

Key Words: nicotine; gastric cancer; ß-adrenergic receptor; protein kinase C; proliferation.


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