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Vol. 19, Issue 8, 3283-3289, August 2008

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DNA-Ligase IV and DNA-Protein Kinase Play a Critical Role in Deficient Caspases Activation in Apoptosis-resistant Cancer Cells by Using Doxorubicin

Claudia Friesen^*, Miriam Uhl, Ulrich Pannicke, Klaus Schwarz, Erich Miltner^*, and Klaus-Michael Debatin

*Institute of Legal Medicine, University of Ulm, 89075 Ulm, Germany; University Children's Hospital, 89075 Ulm, Germany; and Department of Transfusion Medicine, Institute for Clinical Transfusion Medicine, and Institute for Transfusion Medicine and Immunogenetics, University Hospital of Ulm, 89081 Ulm, Germany

Submitted March 20, 2008; Revised May 14, 2008; Accepted May 19, 2008
Monitoring Editor: William P. Tansey

Resistance toward cytotoxic drugs is one of the primary causes for therapeutic failure in cancer therapy. DNA repair mechanisms as well as deficient caspases activation play a critical role in apoptosis resistance of tumor cells toward anticancer drug treatment. Here, we discovered that deficient caspases activation in apoptosis-resistant cancer cells depends on DNA-ligase IV and DNA-protein kinase (DNA-PK), playing crucial roles in the nonhomologous end joining (NHEJ) pathway, which is the predominant pathway for DNA double-strand break repair (DNA-DSB-repair) in mammalian cells. DNA-PK(+/+) as well as DNA-ligase IV (+/+) cancer cells were apoptosis resistant and deficient in activation of caspase-3, caspase-9, and caspase-8 and in cleavage of poly(ADP-ribose) polymerase after doxorubicin treatment. Inhibition of NHEJ by knocking out DNA-PK or DNA-ligase IV restored caspases activation and apoptosis sensitivity after doxorubicin treatment. In addition, inhibition of caspases activation prevented doxorubicin-induced apoptosis but could not prevent doxorubicin-induced DNA damage, indicating that induction of DNA damage is independent of caspases activation. However, caspases activation depends on induction of DNA damage left unrepaired by NHEJ-DNA-DSB-repair. We conclude that DNA damage left unrepaired by DNA-ligase IV or DNA-PK might be the initiator for caspases activation by doxorubicin in cancer cells. Failure in caspases activation using doxorubicin depends on loss of DNA damage and is due to higher rates of NHEJ-DNA-DBS-repair.

Address correspondence to: Claudia Friesen (claudia.friesen{at}uni-ulm.de)