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ToxSci Advance Access published online on September 26, 2006
Toxicological Sciences, 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
Received July 12, 2006
Accepted September 13, 2006

Carcinogenicity

Functional Role of {beta}-adrenergic Receptors in the Mitogenic Action of Nicotine on Gastric Cancer Cells

Vivian Yvonne Shin 1, William Ka Kei Wu 1, Kent Man Chu 2, Marcel Wing Leung Koo 1, Helen Pui Shan Wong 1, Emily Kai Yee Lam 1, Emily Kin Ki Tai 1, and Chi Hin Cho 3 *

1 Department of Pharmacology, The University of Hong Kong, Hong Kong, HKSAR, China
2 Department of Surgery, The University of Hong Kong, Hong Kong, HKSAR, China
3 Department of Pharmacology, The University of Hong Kong, Hong Kong, HKSAR, China; Research Centre of Infection and Immunology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China

* To whom correspondence should be addressed.
Chi Hin Cho, E-mail: chcho{at}hkusua.hku.hk


  Abstract

We previously reported that nicotine promoted gastric cancer cell growth via upregulation of cyclooxygenase (COX)-2. In the present study, we further investigated whether {beta}-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, 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-{beta}I 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 {beta}1- and {beta}2-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 {beta}-adrenoceptors and the downstream PKC-{beta}I / ERK1/2 / COX-2 pathway.

Keywords: nicotine; gastric cancer; beta-adrenergic receptor; protein kinase C; proliferation.
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