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

Stephen M. Weber, Sophia Bornstein, Yuexin Li, Stephen P. Malkoski, Donna Wang, Anil K. Rustgi, Molly Kulesz-Martin, Xiao Jing Wang, Shi Long Lu

Research output: Contribution to journalArticle

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1193-1198
Number of pages6
JournalInternational Journal of Oncology
Issue number5
Publication statusPublished - Nov 2011



  • AKT
  • Head and neck epithelia
  • Head and neck squamous cell carcinoma
  • NNK
  • Tobacco

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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