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Sci Rep ; 11(1): 5665, 2021 03 11.
Article in English | MEDLINE | ID: mdl-33707466

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.


Subject(s)
Brain Neoplasms/metabolism , CDC2 Protein Kinase/metabolism , Glioblastoma/metabolism , NF-kappa B/metabolism , Temozolomide/pharmacology , B-Cell Lymphoma 3 Protein/metabolism , Base Sequence , Binding Sites , Brain Neoplasms/genetics , Brain Neoplasms/pathology , CDC2 Protein Kinase/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Promoter Regions, Genetic/genetics
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