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

Department of Otolaryngology, Oregon Health & Science University, Portland, OR, USA.
International Journal of Oncology (Impact Factor: 3.03). 08/2011; 39(5):1193-8. DOI: 10.3892/ijo.2011.1149
Source: PubMed


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.

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Available from: Shi-Long Lu, Aug 19, 2015
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    • "In addition to the formation of DNA adducts, tobacco carcinogens, such as NNK, activate several signal transduction pathways, including AKT, in both normal and cancer cells in the lung [94]. We have shown that, in both HNSCC tumors and the adjacent mucosa, AKT is activated at a higher frequency in HNSCC patients who are smokers compared to those who are nonsmokers [95]. Also, adding physiologically relevant concentrations of NNK to normal head and neck epithelial cells and HNSCC cell lines will rapidly and constitutively activate AKT in a dose-dependent and time-dependent manner. "
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