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 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1193-1198
Number of pages6
JournalInternational Journal of Oncology
Volume39
Issue number5
DOIs
StatePublished - Nov 2011

Fingerprint

Nitrosamines
Carcinogens
Tobacco
Neck
Epithelium
Head
Phosphorylation
Apoptosis
Glycogen Synthase Kinase 3
Etoposide
Carcinoma, squamous cell of head and neck
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
Carcinogenesis
Mucous Membrane
Epithelial Cells
Cell Line
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone induces AKT activation in head and neck epithelia. / Weber, Stephen M.; Bornstein, Sophia; Li, Yuexin; Malkoski, Stephen P.; Wang, Donna; Rustgi, Anil K.; Kulesz-Martin, Molly; Wang, Xiao Jing; Lu, Shi Long.

In: International Journal of Oncology, Vol. 39, No. 5, 11.2011, p. 1193-1198.

Research output: Contribution to journalArticle

Weber, Stephen M. ; Bornstein, Sophia ; Li, Yuexin ; Malkoski, Stephen P. ; Wang, Donna ; Rustgi, Anil K. ; Kulesz-Martin, Molly ; Wang, Xiao Jing ; Lu, Shi Long. / Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone induces AKT activation in head and neck epithelia. In: International Journal of Oncology. 2011 ; Vol. 39, No. 5. pp. 1193-1198.
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