DNA-dependent protein kinase (DNA-PK) plays a major role in the repair of DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). Lack of DNA-PK causes defective DNA DSB repair and radiosensitization. In general, the cell death induced by IR is considered to be apoptotic. On the other hand, non-apoptotic cell death, autophagy, has recently attracted attention as a novel response of cancer cells to chemotherapy and IR. Autophagy is a protein degradation system, characterized by a prominent formation of double-membrane vesicles in the cytoplasm. Little is known, however, regarding the relationship between DNA-PK and IR-induced autophagy. In the present study, we used human malignant glioma M059J and M059K cells to investigate the role of DNA-PK in IR-induced apoptotic and autophagic cell death. Low-dose IR induced massive autophagic cell death in human malignant glioma M059J cells that do not express the catalytic subunit of DNA-PK (DNA-PKcs). Most M059K cells, the counterpart of M059J cells in which DNA-PKcs is expressed at normal levels, survived and proliferated, although a small portion of the cells underwent apoptosis. The treatment of M059K cells with antisense oligonucleotides against DNA-PKcs (AS-DNA-PKcs) caused radiation-induced autophagy and radiosensitized the cells. Furthermore, AS-DNA-PKcs radiosensitized other malignant glioma cell lines with DNA-PK activity, U373-MG and T98G, by inducing autophagy. The specific inhibition of DNA-PKcs may be promising as a new therapy to radiosensitize malignant glioma cells by inducing autophagy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]