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Induction of Paraptosis: A novel strategy to overcome radiation resistance in cancer cells

Research Project

Project/Area Number 18K15585
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52040:Radiological sciences-related
Research InstitutionUniversity of Toyama

Principal Investigator

REHMAN MATI UR  富山大学, 学術研究部医学系, 特命助教 (10810921)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
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)
KeywordsParaptosis / Radiation / Oxidative stress / Autophagy / Cell death / Cell Death
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.

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.

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (2 results)

All 2019

All Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] Bardoxolone methyl (CDDO-Me or RTA402) induces paraptosis through reactive oxygen species-mediated endoplasmic stress and intracellular calcium release in human colorectal cancer HCT-116 cells2019

    • Author(s)
      Rehman MU, Zhao QL, Refaat A, Jawaid P, Sakurai H, Saitoh JI, Kondo T, Noguchi K.
    • Organizer
      SFRBM 2019 annual conference
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Reactive oxygen species-mediated stress and release of Ca 2+ trigger CDDO-Me induced non-apoptotic/non-autophagic cytoplasmic vacuolation death in colorectal cancer.2019

    • Author(s)
      Rehman MU, Zhao QL, Refaat A, Jawaid P, Sakurai H, Kondo T, Noguchi K.
    • Organizer
      The 72nd Annual Meeting of Society for free Radical Research
    • Related Report
      2019 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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