- Scientific Reports 6, Article number: 22192 (2016)
- doi:10.1038/srep22192
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Abstract
Glycogen
synthase kinase-3β (GSK-3β), a serine/threonine kinase is frequently
inactivated by the oncogenic signalling kinases PI3K/Akt and MAPK/ERK in
diverse malignancies. The present study was designed to investigate
GSK-3β signalling circuits in the 7,12-dimethylbenz[a]anthracene
(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model and the
therapeutic potential of the neem limonoid nimbolide. Inactivation of
GSK-3β by phosphorylation at serine 9 and activation of PI3K/Akt,
MAPK/ERK and β-catenin was associated with increased cell proliferation
and apoptosis evasion during stepwise evolution of HBP carcinomas.
Administration of nimbolide inhibited PI3K/Akt signalling with
consequent activation of GSK-3β thereby inducing trafficking of
β-catenin away from the nucleus and enhancing the expression of miR-126
and let-7. Molecular docking studies confirmed interaction of nimbolide
with PI3K, Akt, ERK and GSK-3β. Furthermore, nimbolide attenuated cell
proliferation and induced apoptosis as evidenced by increased p-cyclin
D1Thr286 and pro-apoptotic proteins. The present study has
unravelled aberrant phosphorylation as a key determinant for oncogenic
signalling and acquisition of cancer hallmarks in the HBP model. The
study has also provided mechanistic insights into the chemotherapeutic
potential of nimbolide that may be a useful addition to the
armamentarium of natural compounds targeting PI3K for oral cancer
treatment.