Molecular Insights to Withaferin-A induced Senescence: Bioinformatics and Experimental Evidence to the Role of NF-kappa B and CARF

Molecular Insights to Withaferin-A induced Senescence: Bioinformatics and Experimental Evidence... Abstract Withaferin-A (Wi-A) has been shown to possess anticancer activity. Molecular mechanism(s) of its action have not been fully resolved. We recruited low dose of Wi-A that caused slow growth arrest in cancer cells, and was relatively safe for normal cells. Consistently, we detected nuclear translocation of NFκB and activation of p38MAPK selectively in cancer cells. Bioinformatics analyses revealed that Wi-A did not disrupt IKK/IKKβ-Nemo complex that regulates NFκB activity. However, it caused moderate change in the conformation of IKKβ-Nemo interacting domain. Experimental data revealed increased level of phosphorylated IκBα in Wi-A treated cells, suggesting an activation of IKK complex that was supported by nuclear translocation of NFκB. Molecular docking analysis showed that Wi-A did not disrupt, however decreased the stability of the NFκB-DNA complex. It was supported by downregulation of DNA-binding and transcriptional activities of NFκB. Further analysis revealed that Wi-A caused upregulation of CARF (Collaborator of ARF) demonstrating an activation of DNA damage oxidative stress response in both cancer and normal cells. In line with this, upregulation of p21WAF1, p16INK4A, hypophoshorylated pRB and induction of senescence was observed demonstrating that Wi-A-induced senescence is mediated by multiple pathways in which CARF-mediated DNA damage and oxidative stress play a major role. Withaferin-A, Cancer, Cellular Senescence, p53-p21 pathway, NFκB, CARF © The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences Oxford University Press

Molecular Insights to Withaferin-A induced Senescence: Bioinformatics and Experimental Evidence to the Role of NF-kappa B and CARF

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
ISSN
1079-5006
eISSN
1758-535X
D.O.I.
10.1093/gerona/gly107
Publisher site
See Article on Publisher Site

Abstract

Abstract Withaferin-A (Wi-A) has been shown to possess anticancer activity. Molecular mechanism(s) of its action have not been fully resolved. We recruited low dose of Wi-A that caused slow growth arrest in cancer cells, and was relatively safe for normal cells. Consistently, we detected nuclear translocation of NFκB and activation of p38MAPK selectively in cancer cells. Bioinformatics analyses revealed that Wi-A did not disrupt IKK/IKKβ-Nemo complex that regulates NFκB activity. However, it caused moderate change in the conformation of IKKβ-Nemo interacting domain. Experimental data revealed increased level of phosphorylated IκBα in Wi-A treated cells, suggesting an activation of IKK complex that was supported by nuclear translocation of NFκB. Molecular docking analysis showed that Wi-A did not disrupt, however decreased the stability of the NFκB-DNA complex. It was supported by downregulation of DNA-binding and transcriptional activities of NFκB. Further analysis revealed that Wi-A caused upregulation of CARF (Collaborator of ARF) demonstrating an activation of DNA damage oxidative stress response in both cancer and normal cells. In line with this, upregulation of p21WAF1, p16INK4A, hypophoshorylated pRB and induction of senescence was observed demonstrating that Wi-A-induced senescence is mediated by multiple pathways in which CARF-mediated DNA damage and oxidative stress play a major role. Withaferin-A, Cancer, Cellular Senescence, p53-p21 pathway, NFκB, CARF © The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The Journals of Gerontology Series A: Biomedical Sciences and Medical SciencesOxford University Press

Published: Apr 28, 2018

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