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Tobacco Carcinogen-Induced Cellular Transformation Increases Akt Activation In Vitro and In Vivo^*

^* From the Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Correspondence to: Phillip Dennis, MD, PhD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 8901 Wisconsin, Ave, Bethesda, MD 20889-5105; e-mail: pdennis{at}nih.gov

Previously, we identified the serine/threonine kinase Akt as a molecular target in lung cancer, because Akt is constitutively active in non-small cell lung cancer cells in vitro and in vivo, and tobacco components activate Akt in primary cultures of human lung epithelial cells. To determine a role for Akt activation in the transformation of lung epithelial cells, we evaluated the PI3K/Akt pathway in immortalized human lung epithelial cells (BEAS-2B cells) or in BEAS-2B cells that were fully transformed by a tobacco-specific carcinogen (ie, BEAS-2B/4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK] cells) in vitro, as well as NNK-induced murine lung lesions in vivo. Adding nicotine or NNK to BEAS-2B or BEAS-2B/NNK cells increased Akt activation in a time-dependent and dose-dependent manner, and increased cellular proliferation. Compared to immortalized BEAS-2B cells, tumorigenic BEAS-2B/NNK cells had higher levels of epidermal growth factor receptor (EGFR) phosphorylation, increased Akt activity, increased phosphorylation of multiple substrates downstream of Akt, and enhanced survival under conditions of serum starvation. Pharmacologic inhibitors of PI3K, Akt, or the EGFR decreased Akt activity and increased apoptosis of BEAS-2B and BEAS-2B/NNK cells, with the greatest relative induction of apoptosis observed with BEAS-2B/NNK cells.

To confirm these results, we infected BEAS-2B and BEAS-2B/NNK cells with adenoviruses expressing dominant-negative Akt. At lower doses of adenoviral infectivity, immortalized BEAS-2B cells underwent greater apoptosis than did BEAS-2B/NNK cells, but at the higher doses each cell type underwent apoptosis. To evaluate a spectrum of tobacco carcinogen-induced preneoplastic and neoplastic lesions in vivo, we performed an immunohistochemical analysis of the PI3K/Akt pathway in lung tissues derived from A/J mice treated with NNK. Active Akt and downstream components were detected in the normal bronchial epithelium, hyperplastic lesions, adenomas, and adenocarcinomas, with the most intense staining observed in adenocarcinomas. Collectively, these results show the following: (1) that tobacco components increase Akt activity and promote the growth of immortalized and tumorigenic lung epithelial cells; (2) that activation of the PI3K/Akt pathway increases with the phenotypic progression of lung epithelial cells caused by a tobacco carcinogen; and (3) that genetic or pharmacologic inhibition of Akt increases the apoptosis of immortalized and tumorigenic lung epithelial cells. These data suggest that therapeutic approaches that inhibit Akt might prevent the phenotypic progression of lung cancer.

	Footnotes

 
Abbreviations: EGFR = epidermal growth factor receptor; NNK = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by West, K. A. Articles by Dennis, P. A. Search for Related Content PubMed PubMed Citation Articles by West, K. A. Articles by Dennis, P. A.