Ku autoantigen affects the susceptibility to anticancer drugs

The Ku70/80 autoantigens (Ku) are the DNA-binding components of a DNA-depen dent protein kinase (PK) involved in DNA double strand breaks repairing a V (D)J recombination. Because apoptosis is associated with DNA fragmentation and, consequently, creation of double strand breaks, and a variety of DNA-d amaging drugs kill tumor cells by apoptosis, we tested the impact of Ku def iciency on the sensitivity of anticancer drugs. Ku-null mutant cell lines K u70(-/-) and Ku80(-/-) were highly sensitive to anticancer drugs, compared with their wild-type cells. Ku-deficient cells were more sensitive to bleom ycin-induced DNA fragmentation and exhibited a higher level of c-jun NH2-ki nase/stress-activated PK activity than mild-type cells, whereas R7080-6 cel ls overexpressing both human Ku70 and Ku80 were resistant to bleomycin-indu ced apoptosis and exhibited a lower level of c-jun NH2-kinase/stress-activa ted PK activity. The Ku-protein level and Ku DNA binding activity were decr eased after treatment with bleomycin, adriamycin, or vincristine, and the d ecreases were blocked by the treatment of z-DEVD-fmk, a specific inhibitor of caspase-3 suggesting that loss of Ku DNA binding is, in part, due to a c aspase-mediated decrease in Ku protein levels. By contrast, HSF1 DNA-bindin g activity was increased by the treatment of these anticancer drugs and, su bsequently, mitochondrial heat shock protein HSP75 was specifically induced . Our data suggest that Ku can affect the susceptibility to anticancer drag -induced apoptosis.