Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 13, Issue 10, Pages 4239-4256Publisher
WILEY
DOI: 10.1111/j.1582-4934.2009.00888.x
Keywords
NF-kappa B; apoptosis; glioblastoma; DNA damage
Categories
Funding
- Deutsche Forschungsgemeinschaft
- European Community
- [IAP6/18]
Ask authors/readers for more resources
NF-kappa B is activated by DNA-damaging anticancer drugs as part of the cellular stress response. However, the consequences of drug-induced NF-kappa B activation are still only partly understood. To investigate the impact of NF-kappa B on the cell's response to DNA damage, we engineered glioblastoma cells that stably express mutant I kappa B alpha superrepressor (I kappa B alpha-SR) to block NF-kappa B activation. Here, we identify a novel pro-apoptotic function of NF-kappa B 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-kappa B DNA binding and transcriptional activity prior to induction of cell death. Importantly, specific inhibition of drug-induced NF-kappa B activation by I kappa B alpha-SR or RNA interference against p65 significantly reduces apoptosis upon treatment with Doxorubicin, Daunorubicin or Mitoxantrone. NF-kappa B exerts this pro-apoptotic function especially after pulse drug exposure as compared to continuous treatment indicating that the contribution of NF-kappa B becomes relevant during the recovery phase following the initial DNA damage. Mechanistic studies show that NF-kappa B inhibition does not alter Doxorubicin uptake and efflux or cell cycle alterations. Genetic silencing of p53 by RNA interference reveals that NF-kappa B promotes drug-induced apoptosis in a p53-independent manner. Intriguingly, drug-mediated NF-kappa B activation results in a significant increase in DNA damage prior to the induction of apoptosis. By demonstrating that NF-kappa B 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-kappa B in glioblastoma.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available