Cargando…
Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis
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 h...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763291/ https://www.ncbi.nlm.nih.gov/pubmed/26902162 http://dx.doi.org/10.1038/srep22192 |
_version_ | 1782417242291437568 |
---|---|
author | Sophia, Josephraj Kiran Kishore T., Kranthi Kowshik, Jaganathan Mishra, Rajakishore Nagini, Siddavaram |
author_facet | Sophia, Josephraj Kiran Kishore T., Kranthi Kowshik, Jaganathan Mishra, Rajakishore Nagini, Siddavaram |
author_sort | Sophia, Josephraj |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4763291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47632912016-03-01 Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis Sophia, Josephraj Kiran Kishore T., Kranthi Kowshik, Jaganathan Mishra, Rajakishore Nagini, Siddavaram Sci Rep Article 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. Nature Publishing Group 2016-02-23 /pmc/articles/PMC4763291/ /pubmed/26902162 http://dx.doi.org/10.1038/srep22192 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Sophia, Josephraj Kiran Kishore T., Kranthi Kowshik, Jaganathan Mishra, Rajakishore Nagini, Siddavaram Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title | Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title_full | Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title_fullStr | Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title_full_unstemmed | Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title_short | Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis |
title_sort | nimbolide, a neem limonoid inhibits phosphatidyl inositol-3 kinase to activate glycogen synthase kinase-3β in a hamster model of oral oncogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763291/ https://www.ncbi.nlm.nih.gov/pubmed/26902162 http://dx.doi.org/10.1038/srep22192 |
work_keys_str_mv | AT sophiajosephraj nimbolideaneemlimonoidinhibitsphosphatidylinositol3kinasetoactivateglycogensynthasekinase3binahamstermodeloforaloncogenesis AT kirankishoretkranthi nimbolideaneemlimonoidinhibitsphosphatidylinositol3kinasetoactivateglycogensynthasekinase3binahamstermodeloforaloncogenesis AT kowshikjaganathan nimbolideaneemlimonoidinhibitsphosphatidylinositol3kinasetoactivateglycogensynthasekinase3binahamstermodeloforaloncogenesis AT mishrarajakishore nimbolideaneemlimonoidinhibitsphosphatidylinositol3kinasetoactivateglycogensynthasekinase3binahamstermodeloforaloncogenesis AT naginisiddavaram nimbolideaneemlimonoidinhibitsphosphatidylinositol3kinasetoactivateglycogensynthasekinase3binahamstermodeloforaloncogenesis |