title: Functional role of beta-adrenergic receptors in the mitogenic action of nicotine on gastric cancer cells.
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 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, 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-betaI 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 beta1- and beta2-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-betaI/ERK1/2/COX-2 pathway.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China.
authors.forename: Vivian Yvonne
authors.initials: VY
authors.lastname: Shin
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.forename: Kent Man
authors.initials: KM
authors.lastname: Chu
authors.forename: Marcel Wing Leung
authors.initials: MW
authors.lastname: Koo
authors.forename: Helen Pui Shan
authors.initials: HP
authors.lastname: Wong
authors.forename: Emily Kai Yee
authors.initials: EK
authors.lastname: Lam
authors.forename: Emily Kin Ki
authors.initials: EK
authors.lastname: Tai
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000503:physiopathology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008934:Mitogens / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis
chemical_list: D000319:Adrenergic beta-Antagonists; D002070:Butadienes; D008565:Membrane Proteins; D008934:Mitogens; D009570:Nitriles; D011412:Propanolamines; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D018808:Transcription Factor AP-1; C113580:U 0126; C026777:ICI 118551; D001262:Atenolol; D009538:Nicotine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; D019311:Staurosporine