Sophia Josephraj, Kiran Kishore T Kranthi, Kowshik Jaganathan, Mishra Rajakishore, Nagini Siddavaram
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi 835205, Jharkhand, India.
Sci Rep. 2016 Feb 23;6:22192. doi: 10.1038/srep22192.
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 D1(Thr286) 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.
糖原合酶激酶-3β（GSK-3β）是一种丝氨酸/苏氨酸激酶，在多种恶性肿瘤中常被致癌信号激酶PI3K/Akt和MAPK/ERK失活。本研究旨在探讨7,12-二甲基苯并[a]蒽（DMBA）诱导的仓鼠颊囊（HBP）致癌模型中的GSK-3β信号通路以及印楝柠檬苦素（nimbolide）的治疗潜力。在HBP癌的逐步演变过程中，丝氨酸9位点磷酸化导致的GSK-3β失活以及PI3K/Akt、MAPK/ERK和β-连环蛋白的激活与细胞增殖增加和凋亡逃避有关。给予nimbolide可抑制PI3K/Akt信号通路，从而激活GSK-3β，进而诱导β-连环蛋白从细胞核中转运出来，并增强miR-126和let-7的表达。分子对接研究证实了nimbolide与PI3K、Akt、ERK和GSK-3β的相互作用。此外，nimbolide可减弱细胞增殖并诱导凋亡，p-细胞周期蛋白D1（Thr286）和促凋亡蛋白增加证明了这一点。本研究揭示了异常磷酸化是HBP模型中致癌信号和癌症特征获得的关键决定因素。该研究还提供了关于nimbolide化疗潜力的机制性见解，nimbolide可能是靶向PI3K用于口腔癌治疗的天然化合物库中的一个有用补充。
