title: Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells.
abstract: Cigarette smoking has been implicated in colon cancer. Nicotine is a major alkaloid in cigarette smoke. In the present study, we showed that nicotine stimulated HT-29 cell proliferation and adrenaline production in a dose-dependent manner. The stimulatory action of nicotine was reversed by atenolol and ICI 118,551, a beta(1)- and beta(2)-selective antagonist, respectively, suggesting the role of beta-adrenoceptors in mediating the action. Nicotine also significantly upregulated the expression of the catecholamine-synthesizing enzymes [tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DbetaH) and phenylethanolamine N-methyltransferase]. Inhibitor of TH, a rate-limiting enzyme in the catecholamine-biosynthesis pathway, reduced the actions of nicotine on cell proliferation and adrenaline production. Expression of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) was demonstrated in HT-29 cells. Methyllycaconitine, an alpha7-nAChR antagonist, reversed the stimulatory actions of nicotine on cell proliferation, TH and DbetaH expression as well as adrenaline production. Taken together, through the action on alpha7-nAChR nicotine stimulates HT-29 cell proliferation via the upregulation of the catecholamine-synthesis pathway and ultimately adrenaline production and beta-adrenergic activation. These data reveal the contributory role alpha7-nAChR and beta-adrenoceptors in the tumorigenesis of colon cancer cells and partly elucidate the carcinogenic action of cigarette smoke on colon cancer.
authors.affiliation: Department of Pharmacology, The University of Hong Kong, Hong Kong, China.
authors.forename: Helen Pui Shan
authors.initials: HP
authors.lastname: Wong
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.forename: Emily Kai Yee
authors.initials: EK
authors.lastname: Lam
authors.forename: Emily Kin Ki
authors.initials: EK
authors.lastname: Tai
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism*; D006801:Humans; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000470:Alkaloids; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011943:Receptors, Adrenergic, beta; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine