Carcinogenesis Advance Access originally published online on March 24, 2005
Carcinogenesis 2005 26(7):1182-1195; doi:10.1093/carcin/bgi072
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Carcinogenesis vol.26 no.7 © Oxford University Press 2005; all rights reserved.
Tobacco components stimulate Akt-dependent proliferation and NF
B-dependent survival in lung cancer cells
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, USA
* To whom correspondence should be addressed at: Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. Tel: +1 301 496 0929; Fax: +1 301 496 0047; Email: pdennis{at}nih.gov
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 
3/4 or 7 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 NF
B-dependent. Collectively, these results identify tobacco component-induced, Akt-dependent proliferation and NFB-dependent survival as cellular processes that could underlie the detrimental effects of smoking in cancer patients.
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