title: Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis.
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 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.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
authors.forename: Josephraj
authors.initials: J
authors.lastname: Sophia
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
authors.forename: Kranthi
authors.initials: K
authors.lastname: Kiran Kishore T
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Kowshik
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi 835205, Jharkhand, India.
authors.forename: Rajakishore
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000737:chemistry / Q000378:metabolism*; D036701:Limonins / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D008647:Mesocricetus; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009062:Mouth Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D036701:Limonins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C042198:nimbolide