Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia

  • Authors: Stephen M. Weber, Sophia Bornstein, Yuexin Li, Stephen P. Malkoski, Donna Wang, Anil K. Rustgi, Molly F. Kulesz-Martin, Xiao-Jing Wang, Shi-Long Lu
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  • Published online on: Friday, August 5, 2011
  • Pages: 1193-1198
  • DOI: 10.3892/ijo.2011.1149

Abstract

Exposure to tobacco carcinogens is causally associated with head and neck squamous cell carcinoma (HNSCC), but the underlying molecular mechanisms remain unclear. Here, we reported that AKT is activated at a higher frequency in both HNSCC tumors and the adjacent mucosa from HNSCC patients who are smokers than those from HNSCC patients who are non-smokers. Adding physiologically relevant concentrations of 4-(methylnitrosamino)-1-(3-pyridyl)-1-1butanone (NNK), a major tobacco carcinogen, to normal head and neck epithelial cells and HNSCC cell lines, rapidly and constitutively activated AKT through phosphorylation in a dose- and time-dependent manner. AKT phosphorylation was associated with activation of downstream signaling mediators BAD, MDM2, GSK-3β, mTOR. These alterations correlated with increased proliferation and decreased etoposide-induced apoptosis in NNK-exposed cells. Finally, NNK exposure to mouse head and neck epithelia resulted in epithelial hyperproliferation and reduced apoptosis, which is correlated with AKT activation. Our results suggest that AKT activation is an early event and plays a pivotal role in mediating tobacco-induced HNSCC carcinogenesis.
Journal Cover

November 2011
Volume 39 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

2012 Impact Factor: 2.773
Ranked #30/202 Oncology
(total number of cites)

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APA
Weber, S., Bornstein, S., Li, Y., Malkoski, S., Wang, D., Rustgi, A., Kulesz-Martin, M., Wang, X., & Lu, S. (2011). Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia. International Journal of Oncology, 39(5), 1193-1198.
MLA
Weber, Bornstein, Li, Malkoski, Wang, Rustgi, Kulesz-Martin, Wang, and Shi-Long Lu. "Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia." International Journal of Oncology International Journal of Oncology 39.5 (2011): 1193-1198.
Chicago
Weber, Bornstein, Li, Malkoski, Wang, Rustgi, Kulesz-Martin, Wang, and Shi-Long Lu. "Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia." International Journal of Oncology International Journal of Oncology 39 no. 5 (2011): 1193-1198.