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

Sci Rep. 2021 Mar 11;11(1):5665. doi: 10.1038/s41598-021-84912-4.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • NF-kappa B
  • CDC2 Protein Kinase
  • Temozolomide