title: Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia.
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.
authors.affiliation: Department of Otolaryngology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Weber
authors.forename: Sophia
authors.initials: S
authors.lastname: Bornstein
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Malkoski
authors.forename: Donna
authors.initials: D
authors.lastname: Wang
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Molly F
authors.initials: MF
authors.lastname: Kulesz-Martin
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009602:Nitrosamines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051057:Proto-Oncogene Proteins c-akt