Inhibition of the DNA-Dependent Protein Kinase Catalytic Subunit Radiosensitizes Malignant Glioma Cells by Inducing Autophagy
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- Shigeru Daido
- 1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and
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- Akitsugu Yamamoto
- 2Department of Cell Biology and Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga, Japan
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- Keishi Fujiwara
- 1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and
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- Raymond Sawaya
- 1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and
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- Seiji Kondo
- 1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and
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- Yasuko Kondo
- 1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and
Abstract
<jats:title>Abstract</jats:title> <jats:p>DNA-dependent protein kinase (DNA-PK) plays a major role in the repair of DNA double-strand breaks induced by ionizing radiation (IR). Lack of DNA-PK causes defective DNA double-strand break repair and radiosensitization. In general, the cell death induced by IR is considered to be apoptotic. On the other hand, nonapoptotic 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 M059J cells that lack the catalytic subunit of DNA-PK (DNA-PKcs). Most M059K cells, the counterpart of M059J cells in which DNA-PKcs are expressed at normal levels, survived, and proliferated although a small portion of the cells underwent apoptosis. Low-dose IR inhibited the phosphorylation of p70S6K, a molecule downstream of the mammalian target of rapamycin associated with autophagy in M059J cells but not in M059K cells. The treatment of M059K cells with antisense oligonucleotides against DNA-PKcs caused radiation-induced autophagy and radiosensitized the cells. Furthermore, antisense oligonucleotides against 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.</jats:p>
Journal
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- Cancer Research
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Cancer Research 65 (10), 4368-4375, 2005-05-15
American Association for Cancer Research (AACR)
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Keywords
Details 詳細情報について
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- CRID
- 1363951795572964864
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- NII Article ID
- 30018588885
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- ISSN
- 15387445
- 00085472
- http://id.crossref.org/issn/00085472
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- Data Source
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- Crossref
- CiNii Articles