CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma

Abstract The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphoryl...

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Autores principales:	David J. Voce, Giovanna M. Bernal, Kirk E. Cahill, Longtao Wu, Nassir Mansour, Clayton D. Crawley, Paige-Ashley S. Campbell, Ainhoa Arina, Ralph R. Weichselbaum, Bakhtiar Yamini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a43b98628f924851b3c674791b7711df
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spelling	oai:doaj.org-article:a43b98628f924851b3c674791b7711df2021-12-02T13:34:51ZCDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma10.1038/s41598-021-84912-42045-2322https://doaj.org/article/a43b98628f924851b3c674791b7711df2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84912-4https://doaj.org/toc/2045-2322Abstract The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.David J. VoceGiovanna M. BernalKirk E. CahillLongtao WuNassir MansourClayton D. CrawleyPaige-Ashley S. CampbellAinhoa ArinaRalph R. WeichselbaumBakhtiar YaminiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David J. Voce Giovanna M. Bernal Kirk E. Cahill Longtao Wu Nassir Mansour Clayton D. Crawley Paige-Ashley S. Campbell Ainhoa Arina Ralph R. Weichselbaum Bakhtiar Yamini CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
description	Abstract The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.
format	article
author	David J. Voce Giovanna M. Bernal Kirk E. Cahill Longtao Wu Nassir Mansour Clayton D. Crawley Paige-Ashley S. Campbell Ainhoa Arina Ralph R. Weichselbaum Bakhtiar Yamini
author_facet	David J. Voce Giovanna M. Bernal Kirk E. Cahill Longtao Wu Nassir Mansour Clayton D. Crawley Paige-Ashley S. Campbell Ainhoa Arina Ralph R. Weichselbaum Bakhtiar Yamini
author_sort	David J. Voce
title	CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
title_short	CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
title_full	CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
title_fullStr	CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
title_full_unstemmed	CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
title_sort	cdk1 is up-regulated by temozolomide in an nf-κb dependent manner in glioblastoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a43b98628f924851b3c674791b7711df
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CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma

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