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.
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.
Crowley-Weber
Cara L
CL
Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Dvorakova
Katerina
K
Crowley
Cheray
C
Bernstein
Harris
H
Bernstein
Carol
C
Garewal
Harinder
H
Payne
Claire M
CM
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
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