2005 Fiscal Year Final Research Report Summary
Radiation sensitization of cancer cells by RNA interference
| Project/Area Number |
16591220
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | Nara Medical University School of Medicine |
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Principal Investigator |
OHNISHI Ken Nara Medical University, Department of Biology, Associate Professor, 医学部, 助教授 (50152195)
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| Project Period (FY) |
2004 – 2005
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| Keywords | NBS1 / XIAP / NF-κB / siRNA / radiation / DNA-repair / cell survival / sensitization |
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| Research Abstract |
NBS 1 is essential for the repair of radiation induced DNA double-strand breaks (DSBs) in yeast and higher vertebrate cells. In this paper, we examined whether suppressed NBS1 expression by small interference RNA (siRNA) could enhance radiation sensitivity in cancer cells with different p53 status. We used human non-small cell lung cancer cells, differing in p53 gene status (H1299/wtp53 cells bearing wild-type p53 or H1299/mp53 cells bearing mutant p53). A DNA cassette expressing siRNA targeted for the NBS1 gene was transfected into those cell lines and radiation sensitivity was examined with a colony-forming assay. Cellular levels of NBS1 and other proteins were analyzed using Western blot. We found that the radiation sensitivity of H1299/wtp53 and H1299/mp53 cells was enhanced by transfection of the DNA cassette. In the NBS1-siRNA transfected cells, we observed decreased constitutive expression of NBS1 protein and decreased radiation-induced accumulation of phosphorylated NBS1 protein. In addition, radiation-induced expression of the transcription factor NF-κB and XIAP (X-chromosome-linked inhibitor of apoptosis protein) was suppressed by NBS1-siRNA. Enhanced X-ray, sensitivity, after NBS1-siRNA transfection, was achieved in p53 wild-type and even more pronounced in p53 mutant cells. The transfection of siRNA targeted for XIAP also enhanced X-ray sensitivity even more pronounced for p53 mutant cells compared to p53 wild-type cells. Our data suggest that the sensitization to radiation is a result of NBS1-siRNA-mediated suppression of X-ray-induced cell-survival signaling pathways via NF-κB and XIAP and that it is a novel radiation therapy-sensitizing agent, particularly in human p53 mutant cancer cells.
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[Journal Article] Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on quiescent tumor cells and the dependency on p53 status of rumor cells.2005
Author(s)
Masunaga S., Nagasawa H., Uto Y., Hori H., Ohnishi K., Takahashi A., Ohnishi T., Suzuki M., Nagata K., Kinashi Y., Ono K.
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Journal Title
Oncology Reports 14
Pages: 393-400
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Evidence for the involvement of double-stand breaks in heat-induced cell killing.2004
Author(s)
Takahashi A., Matsumoto H., Nagayama K., Kitano M., Hirose S., Tanaka H., Mori E., Yamakawa N., Yasumoto J., Yuki K., Ohnishi K., Ohnishi T.
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Journal Title
Cancer Research 64
Pages: 8839-8845
Description
「研究成果報告書概要(欧文)」より
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