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Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells
Kip A. West, … , Steven Belinsky, Phillip A. Dennis
Kip A. West, … , Steven Belinsky, Phillip A. Dennis
Published January 1, 2003
Citation Information: J Clin Invest. 2003;111(1):81-90. https://doi.org/10.1172/JCI16147.
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Article Oncology

Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells

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Abstract

Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon α3-/α4-containing or α7-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70S6K, 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis.

Authors

Kip A. West, John Brognard, Amy S. Clark, Ilona R. Linnoila, Xiaowei Yang, Sandra M. Swain, Curtis Harris, Steven Belinsky, Phillip A. Dennis

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Figure 3

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Effect of nAchR antagonists on nicotinic activation of Akt in NHBEs and ...
Effect of nAchR antagonists on nicotinic activation of Akt in NHBEs and SAECs. (a) Nicotine. Only LY294002 or the α3/α4 antagonist DHβE inhibited nicotine-induced Akt phosphorylation in NHBEs (upper left panels) and SAECs (lower panels). To confirm the role of α3 nAchRs in activating Akt in NHBEs, α-ATX (an α3 agonist) was added to NHBEs with or without DHβE (upper right panels). (b) NNK. In contrast to nicotine-mediated Akt phosphorylation, NNK-induced phosphorylation in NHBEs was inhibited by LY294002, the α7 antagonists α-BTX and MLA, and the nonspecific inhibitor MCA. DHβE was ineffective.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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