2006 Fiscal Year Final Research Report Summary
Radiosensitization of hypoxic cancer cells by activation of mTOR signaling
| Project/Area Number |
17591314
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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 | Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka Prefectural Hospital Organization |
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Principal Investigator |
MUKAI Mutsuko Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka Prefectural Hospital Organization, Biochemistry, Principal investigator, 研究所, 主任研究員 (20342991)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Masahiro Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka Prefectural Hospital Organization, Biochemistry, director, 研究所, 総括研究員 (10342990)
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| Project Period (FY) |
2005 – 2006
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| Keywords | hypoxia / mTOR / PI3K / apoptosis / radiosensitization |
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| Research Abstract |
mTOR (mammalian target of rapamycin) is activated and contributes to proliferation and survival of cancer cells under oxygenated and nutritionally rich conditions. On the other hand, under hypoxic and nutritionally poor conditions, mTOR signal is suppressed, although the physiological role of the suppression had not been clarified. This study aimed at elucidating the correlation between mTOR signaling and radiosensitivity under hypoxic conditions.
We examined a human cancer cell line, AsPC-1, which was hypoxia resistant. IGF treatment increased mTOR activity and radiosensitivity in parallel under hypoxic conditions. Inhibition of PI3K or mTOR activity by LY294002 or rapamycin decreased radiosensitivity. These results suggest that mTOR signaling affects radiosensitivity in opposite way under normoxia and hypoxia. We also found that IGF stimulation generate endoplasmic reticulum stress under hypoxic conditions, and that CHOP played critical role in cell death (Cancer Research, in revision). CHOP was necessary for the induction of apoptosis by IGF treatment under hypoxic conditions.
We also tried TAT-ODD system equipped with active form of Rheb. AsPC-1 cells treated with TAT-ODD-rheb could not stimulate mTOR signaling under hypoxic conditions. In AsPC-1 cells, other factors in addition to rheb are necessary to activate mTOR signaling under hypoxic conditions. Radiosensitization by activating mTOR signaling under hypoxic area in vivo remains to be elucidated.
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