title: Nicotine, through upregulating pro-survival signaling, cooperates with NNK to promote transformation.
abstract: Cigarette smoking is a mixture of thousands of compounds, many of which are carcinogens, such as NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Nicotine, as an addictive substance in cigarette, has been shown to promote growth of non-neuronal cells. It is unclear how nicotine cooperates with tobacco-related carcinogens during tumorigenesis. Here, by concurrent treatment of nicotine and NNK, we investigate the effect of the cooperation of these two compounds on cell growth and apoptosis in various different lung epithelial (RLE) or cancer (LKR) cells. We demonstrated that short-term nicotine exposure moderately activated mitogenic signaling pathways (such as PKC, ERK, and Akt) and a mediocre protection against cisplatin-mediated apoptosis. In contrast, NNK strongly stimulated mitogenic signaling and rendered the cells a high resistance to cisplatin. The pre-ligation of nAChR by nicotine interfered with NNK-mediated mitogenic signaling and resistance to cisplatin, the magnitude of which was similar as that exposed to nicotine alone. Interestingly, a week after the exposure to nicotine or nicotine plus NNK, Bcl-2 expression was augmented, accompanied with the increased resistance to cisplatin-induced apoptosis. In comparison, long-term NNK treatment provided very little protection of the cells from cisplatin. We also showed that the combination treatment promoted more cells to grow in an anchorage-independent fashion than NNK exposure alone. Thus, the data suggest that through occupying nAChR, nicotine appears to modulate NNK-mediated signaling and persistently sustain pro-survival activities to promote transformation.
authors.affiliation: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishioka
authors.forename: Jinjin
authors.initials: J
authors.lastname: Guo
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.forename: Petra
authors.initials: P
authors.lastname: Huppi
authors.forename: Chang Yan
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D053938:DNA Fragmentation; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D018722:Nicotinic Agonists; D009602:Nitrosamines; D011978:Receptors, Nicotinic; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002945:Cisplatin