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

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-kappa B via a putative kappa B-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor kappa B protein, BCL-3. Treatment with TMZ induced binding of NF-kappa B to the kappa B-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the kappa B-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-kappa B 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.

Automated summary

The alkylating agent TMZ is commonly used in chemotherapeutic treatment of GBM. TMZ induces CDK1 expression via NF-κB regulation, enhancing its cytotoxic effect. Targeting CDK1, regulated by p50 and BCL-3, may improve TMZ efficacy against GBM.