Identification of a novel pro‐apopotic function of NF‐κB in the DNA damage response

NF‐κB is activated by DNA‐damaging anticancer drugs as part of the cellular stress response. However, the consequences of drug‐induced NF‐κB activation are still only partly understood. To investigate the impact of NF‐κB on the cell’s response to DNA damage, we engineered glioblastoma cells that stably express mutant IκBα superrepressor (IκBα‐SR) to block NF‐κB activation. Here, we identify a novel pro‐apoptotic function of NF‐κB in the DNA damage response in glioblastoma cells. Chemotherapeutic drugs that intercalate into DNA and inhibit topoisomerase II such as Doxorubicin, Daunorubicin and Mitoxantrone stimulate NF‐κB DNA binding and transcriptional activity prior to induction of cell death. Importantly, specific inhibition of drug‐induced NF‐κB activation by IκBα‐SR or RNA interference against p65 significantly reduces apoptosis upon treatment with Doxorubicin, Daunorubicin or Mitoxantrone. NF‐κB exerts this pro‐apoptotic function especially after pulse drug exposure as compared to continuous treatment indicating that the contribution of NF‐κB becomes relevant during the recovery phase following the initial DNA damage. Mechanistic studies show that NF‐κB inhibition does not alter Doxorubicin uptake and efflux or cell cycle alterations. Genetic silencing of p53 by RNA interference reveals that NF‐κB promotes drug‐induced apoptosis in a p53‐independent manner. Intriguingly, drug‐mediated NF‐κB activation results in a significant increase in DNA damage prior to the induction of apoptosis. By demonstrating that NF‐κB promotes DNA damage formation and apoptosis upon pulse treatment with DNA intercalators, our findings provide novel insights into the control of the DNA damage response by NF‐κB in glioblastoma.