title: Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells.
abstract: Retrospective studies have shown that patients with tobacco-related cancers who continue to smoke after their diagnoses have lower response rates and shorter median survival compared with patients who stop smoking. To provide insight into the biologic basis for these clinical observations, we tested whether two tobacco components, nicotine or the tobacco-specific carcinogen, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), could activate the Akt pathway and increase lung cancer cell proliferation and survival. Nicotine or NNK, rapidly and potently, activated Akt in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) cells. Nicotinic activation of Akt increased phosphorylation of multiple downstream substrates of Akt in a time-dependent manner, including GSK-3, FKHR, tuberin, mTOR and S6K1. Since nicotine or NNK bind to cell surface nicotinic acetylcholine receptors (nAchR), we used RT-PCR to assess expression of nine alpha and three beta nAchR subunits in five NSCLC cell lines and two types of primary lung epithelial cells. NSCLC cells express multiple nAchR subunits in a cell line-specific manner. Agonists of alpha3/alpha4 or alpha7 subunits activated Akt in a time-dependent manner, suggesting that tobacco components utilize these subunits to activate Akt. Cellular outcomes after nicotine or NNK administration were also assessed. Nicotine or NNK increased proliferation of NSCLC cells in an Akt-dependent manner that was closely linked with changes in cyclin D1 expression. Despite similar induction of proliferation, only nicotine decreased apoptosis caused by serum deprivation and/or chemotherapy. Protection conferred by nicotine was NFkappaB-dependent. Collectively, these results identify tobacco component-induced, Akt-dependent proliferation and NFkappaB-dependent survival as cellular processes that could underlie the detrimental effects of smoking in cancer patients.
authors.affiliation: Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, USA.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: S Sianna
authors.initials: SS
authors.lastname: Castillo
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Granville
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sayyah
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival; D005731:Ganglionic Stimulants / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000494:pharmacology*; D009538:Nicotine / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D012907:Smoking / Q000009:adverse effects*; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D005731:Ganglionic Stimulants; D016328:NF-kappa B; D009602:Nitrosamines; D011518:Proto-Oncogene Proteins; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt