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Functional Role of b-Adrenergic Receptors in the - Toxicological ...

Functional Role of b-Adrenergic Receptors in the - Toxicological ...

Functional Role of b-Adrenergic Receptors in the - Toxicological

TOXICOLOGICAL SCIENCES 96(1), 21–29 (2007) doi:10.1093/toxsci/kfl118 Advance Access publication September 26, 2006 Functional Role of b-Adrenergic Receptors in the Mitogenic Action of Nicotine on Gastric Cancer Cells Vivian Yvonne Shin,* William Ka Kei Wu,* Kent Man Chu,† Marcel Wing Leung Koo,* Helen Pui Shan Wong,* Emily Kai Yee Lam,* Emily Kin Ki Tai,* and Chi Hin Cho* , ‡ ,1 *Department of Pharmacology, †Department of Surgery, and ‡Research Centre of Infection and Immunology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China 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 b-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-bI 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 b 1- and b 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 b-adrenoceptors and the downstream PKC-bI/ ERK1/2/COX-2 pathway. Key Words: nicotine; gastric cancer; b-adrenergic receptor; protein kinase C; proliferation. Gastric cancer is the second most common cause of cancer mortalities in males and the fourth in females. Though the incidence of gastric cancer has been decreasing, it remains a common malignancy worldwide, especially in Asia. Cigarette smoking contributes to the increased risk of gastric cancer, with a 1.5- to 2.5-fold increase in the incidence among current smokers (Sasazuki et al., 2002; Stadtlander and Waterbor, 1999). Cigarette smoking is therefore considered to be one of the major risk factors for gastric cancer. Cigarette smoke con- 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: þ852-2817-0859. E-mail: chcho@hkusua.hku.hk. Received July 12, 2006; accepted September 13, 2006 Ó 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 tains many carcinogens that have been shown to induce neoplastic lesions in humans or animals (Stadtlander and Waterbor, 1999). Any defined active component involved in the carcinogenesis of stomach, however, has yet to be identified. Evolving evidence suggests that dysregulation of cyclooxygenase 2 (COX-2) expression may be centrally involved in the pathogenesis of gastric cancer. For instance, COX-2 expression is highly upregulated in cancerous tissues (> 70%) when compared with the normal surrounding tissues (Kawabe et al., 2002). Moreover, nonsteroidal anti-inflammatory drugs are used clinically to treat gastrointestinal cancers, owing to their ability to inhibit COX activity (Jiang and Wong, 2003; Koehne and Dubois, 2004). In this connection, the specific COX-2 inhibitor SC-236 has been reported to suppress gastric cancer cell growth through inhibition of c-jun N-terminal kinase (JNK) activity (Wong et al., 2004). Nimesulide, another selective COX-2 inhibitor, also induced G0/G1 cell cycle arrest and apoptosis in the gastric cancer cell line SGC7901 (Li et al., 2003). In relation to smoking-related malignancies, we previously reported that nicotine, a major component in cigarette, enhanced gastric cancer development by promoting cancer cell proliferation via upregulation of COX-2 (Shin et al., 2004). The mechanism by which nicotine regulates COX-2 expression in gastric cancer cells, however, remains poorly defined. Mitogens and growth factors bind to the cell-surface receptor to initiate cellular responses, such as cell proliferation and differentiation, which may contribute to cell transformation and cancer development. Protein kinase C (PKC), in this regard, has been shown to participate in various cellular signaling pathways that regulate cell proliferation, tumor promotion, differentiation, and apoptosis (Hug and Sarre, 1993). Tumor promoters like phorbol esters and some carcinogens in cigarette smoke (e.g., hydroquinone, catechol, and nitrosamines) are known to activate PKC (Gopalakrishna et al., 1994; Schuller, 1994). To date, 12 isoforms of PKC have been identified, namely, conventional PKC isoforms (a, bI, bII, and c), novel PKC isoforms (d, e, g, and h), atypical PKC isoforms (i, k, and f), and another subgroup PKC (l). The localization and activation properties of these isoforms determine their Downloaded from http://toxsci.oxfordjournals.org/ by guest on December 22, 2012

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