Abstract
Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen contained in cigarette smoke. NNK significantly contributes to smoking-related lung cancer, but the molecular mechanism remains enigmatic. Bcl2 and c-Myc are two major oncogenic proteins that cooperatively promote tumor development. We report here that NNK simultaneously stimulates Bcl2 phosphorylation exclusively at Ser(70) and c-Myc at Thr(58) and Ser(62) through activation of both ERK1/2 and PKCalpha, which is required for NNK-induced survival and proliferation of human lung cancer cells. Treatment of cells with staurosporine or PD98059 blocks both Bcl2 and c-Myc phosphorylation and results in suppression of NNK-induced proliferation. Specific depletion of c-Myc expression by RNA interference retards G(1)/S cell cycle transition and blocks NNK-induced cell proliferation. Phosphorylation of Bcl2 at Ser(70) promotes a direct interaction between Bcl2 and c-Myc in the nucleus and on the outer mitochondrial membrane that significantly enhances the half-life of the c-Myc protein. Thus, NNK-induced functional cooperation of Bcl2 and c-Myc in promoting cell survival and proliferation may occur in a novel mechanism involving their phosphorylation, which may lead to development of human lung cancer and/or chemoresistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Bungarotoxins / pharmacology
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Carcinogens / pharmacology*
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Carcinoma, Small Cell*
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Cell Division / drug effects
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Cell Line, Tumor / cytology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cell Nucleus / metabolism
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Cell Survival / drug effects
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Cisplatin / pharmacology
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Humans
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Lung Neoplasms*
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Nitrosamines / pharmacology*
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Phosphorylation
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Protein Kinase C / metabolism
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Protein Kinase C-alpha
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA, Small Interfering
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Receptors, Nicotinic
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Signal Transduction / drug effects
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Staurosporine / pharmacology
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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Antineoplastic Agents
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Bungarotoxins
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Carcinogens
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Chrna7 protein, human
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Enzyme Inhibitors
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Flavonoids
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Nitrosamines
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Receptors, Nicotinic
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alpha7 Nicotinic Acetylcholine Receptor
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4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
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PRKCA protein, human
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Protein Kinase C
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Protein Kinase C-alpha
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Staurosporine
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Cisplatin
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one