title: Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis.
abstract: Epidemiologic studies indicate that environmental (smoking) and dietary factors (high fat) contribute to carcinogenesis in many organ systems. The aim of our study was to test the hypothesis that nicotine, a component of cigarette smoke, and sodium deoxycholate (NaDOC), a cytotoxic bile salt that increases in concentration in the gastrointestinal tract after a high fat meal, induce similar cellular stresses and that nicotine may enhance some of the NaDOC-induced stresses. We found that nicotine, at 0.8 microM, the very low sub-micromolar level occurring in the tissues of smokers: (1). increases oxidative stress; (2). activates NF-kappaB, a redox-sensitive transcription factor; (3). activates the 78 kD glucose regulated protein promoter, an indication of endoplasmic reticulum stress; (4). induces apoptosis; (5). enhances the ability of NaDOC to activate the 153 kD growth arrest and DNA damage promoter, an indication of increased genotoxic stress; and (6). enhances the ability of NaDOC to activate the xenobiotic response element. Our findings have applicability to G.I. cancer, in general, since smoking is a risk factor in the development of esophageal, pancreatic, gastric and colon cancer, and these cancers are also promoted by bile acids.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Crowley-Weber
authors.forename: Katerina
authors.initials: K
authors.lastname: Dvorakova
authors.forename: Cheray
authors.initials: C
authors.lastname: Crowley
authors.forename: Harris
authors.initials: H
authors.lastname: Bernstein
authors.forename: Carol
authors.initials: C
authors.lastname: Bernstein
authors.forename: Harinder
authors.initials: H
authors.lastname: Garewal
authors.forename: Claire M
authors.initials: CM
authors.lastname: Payne
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology; D004249:DNA Damage; D003840:Deoxycholic Acid / Q000633:toxicity*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D006360:Heat-Shock Proteins; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D018832:Molecular Chaperones / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009153:Mutagens; D016328:NF-kappa B; D014157:Transcription Factors; D015262:Xenobiotics; D003840:Deoxycholic Acid; D051742:Transcription Factor CHOP; D009538:Nicotine; D015500:Chloramphenicol O-Acetyltransferase