TY - JOUR
T1 - Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone induces AKT activation in head and neck epithelia
AU - Weber, Stephen M.
AU - Bornstein, Sophia
AU - Li, Yuexin
AU - Malkoski, Stephen P.
AU - Wang, Donna
AU - Rustgi, Anil K.
AU - Kulesz-Martin, Molly F.
AU - Wang, Xiao Jing
AU - Lu, Shi Long
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
KW - AKT
KW - Head and neck epithelia
KW - Head and neck squamous cell carcinoma
KW - NNK
KW - Tobacco
UR - http://www.scopus.com/inward/record.url?scp=80053213076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053213076&partnerID=8YFLogxK
U2 - 10.3892/ijo.2011.1149
DO - 10.3892/ijo.2011.1149
M3 - Article
C2 - 21822536
AN - SCOPUS:80053213076
SN - 1019-6439
VL - 39
SP - 1193
EP - 1198
JO - International Journal of Oncology
JF - International Journal of Oncology
IS - 5
ER -