Functional role of beta-adrenergic receptors in the mitogenic action of nicotine on gastric cancer cells.
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.
Shin
Vivian Yvonne
VY
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China.
Wu
William Ka Kei
WK
Chu
Kent Man
KM
Koo
Marcel Wing Leung
MW
Wong
Helen Pui Shan
HP
Lam
Emily Kai Yee
EK
Tai
Emily Kin Ki
EK
Cho
Chi Hin
CH
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
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