| Project/Area Number |
18K15585
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52040:Radiological sciences-related
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| Research Institution | University of Toyama |
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Principal Investigator |
REHMAN MATI UR 富山大学, 学術研究部医学系, 特命助教 (10810921)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | Paraptosis / Radiation / Oxidative stress / Autophagy / Cell death / Cell Death |
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| Outline of Final Research Achievements |
In this study, we report for the first time that bardoxolone methyl (CDDO-Me), induces paraptosis in HCT-116 colorectal cancer cells, by promoting vacuolation that results from the endoplasmic reticulum (ER). Induction of ROS by CDDO-Me triggers ER-stress signaling, as paraptosis with cytoplasmic vacuolation could be blocked by an antioxidant N-acetylcysteine (NAC). Mechanistic investigation revealed that the indigenous level of known paraptosis inhibitor, Alix/AIP-1 was down-regulated by CDDO-Me treatment. Besides, Cycloheximide prevents CDDO-Me-induced vacuolation and cell death, indicating the requirement of active de-novo protein synthesis. Notably, this cytoplasmic vacuolation was brought out by a lack of caspase activation or PARP cleavage and DNA fragmentation. CDDO-Me persistently induces the expression of autophagy marker LC3-II, along with ER stress markers, Bip, and CHOP. CDDO-Me mediated paraptosis in HCT-116 cells show potential therapeutic effects.
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| Academic Significance and Societal Importance of the Research Achievements |
Benefits of Selective cancer cell killing with lesser side effects are obvious on the quality of life in cancer patients. The determination of novel agents which can induced cell death particularly in cancer and protect normal tissue will help to provide a new paradigm in the field of oncology.
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