Ku autoantigen affects the susceptibility to anticancer drugs

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 16; pp. 4012 - 4017
• Main Authors: SUN HEE KIM, DOOHA KIM, JEONG SIL HAN, CHOON SIK JEONG, BYUNG SEON CHUNG, CHI DUG KANG, LI, G. C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.1999
• Subjects: Animals; Antigens, Nuclear; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Autoantigens - immunology; Biological and medical sciences; Chemotherapy; DNA Helicases; DNA Repair - immunology; DNA-Binding Proteins - immunology; Drug Resistance, Neoplasm - immunology; HeLa Cells; Humans; Ku Autoantigen; Medical sciences; Mice; Nuclear Proteins - immunology; Pharmacology. Drug treatments; Antineoplastic agent; Rat; Gene product; Doxorubicin; Alkaloid; Bleomycin; Glycopeptide; Established cell line; Tumor cell; Human; Squamous cell carcinoma; Enzyme; Transferases; Rodentia; Malignant tumor; Gene expression; In vitro; Vincristine; Biological activity; Resistance; Vertebrata; Mammalia; Autoantigen; Protein kinase; Animal; Anthracyclins; Fibroblast; Apoptosis
• ISSN: 0008-5472; 1538-7445

The Ku70/80 autoantigens (Ku) are the DNA-binding components of a DNA-dependent 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-damaging drugs kill tumor cells by apoptosis, we tested the impact of Ku deficiency on the sensitivity of anticancer drugs. Ku-null mutant cell lines Ku70-/- and Ku80-/- were highly sensitive to anticancer drugs, compared with their wild-type cells. Ku-deficient cells were more sensitive to bleomycin-induced DNA fragmentation and exhibited a higher level of c-jun NH2-kinase/stress-activated PK activity than wild-type cells, whereas R7080-6 cells overexpressing both human Ku70 and Ku80 were resistant to bleomycin-induced apoptosis and exhibited a lower level of c-jun NH2-kinase/stress-activated PK activity. The Ku-protein level and Ku DNA binding activity were decreased after treatment with bleomycin, adriamycin, or vincristine, and the decreases 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 caspase-mediated decrease in Ku protein levels. By contrast, HSF1 DNA-binding activity was increased by the treatment of these anticancer drugs and, subsequently, mitochondrial heat shock protein HSP75 was specifically induced. Our data suggest that Ku can affect the susceptibility to anticancer drug-induced apoptosis.