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Regulation mechanism of apoptosis-inducing death receptor localization allowing for survival in tumor cells

Research Project

Project/Area Number 19K07648
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJuntendo University

Principal Investigator

Kojima Yuko  順天堂大学, 大学院医学研究科, 助教 (60231312)

Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
KeywordsTumor cells / Cell deth / DR5 / Localization / Nucleus / Intracellular transport / Cancer therapy / SUMOylation / 腫瘍細胞 / 細胞死 / 局在 / 核 / 細胞膜 / 細胞内輸送 / SUMO化 / ゴルジ装置 / タンパク質発現調節 / TRAIL / DR5 localization / TRAIL-resistant tumor / Importin β1 inhibition / Agonistic antibody / 局在制御 / アポトーシス / 分子標的がん治療
Outline of Research at the Start

TRAIL (TNF-related apoptosis-inducing ligand) は正常細胞を除く腫瘍細胞に細胞死を誘導し,副作用の少ない抗腫瘍効果が期待される分子である.TRAILと細胞表面膜で結合して死のシグナルを伝達するDR5 (Death receptor 5) は,TRAIL耐性ヒト腫瘍細胞では主に核に発現して細胞死を免れ,DR5を核内へ運搬するインポーチン(Imp)beta1の働きを抑えると,腫瘍細胞死が誘導される.では,なぜ腫瘍細胞は自身に細胞死をもたらすタンパク質の局在を変えて生存を獲得できるのか,DR5 の局在を決定する分子を同定して新たながん治療への応用を考える.

Outline of Final Research Achievements

DR5 is known to bind TRAIL at the plasma membrane and induces cell death against tumor cells without affecting normal cells. In addition, DR5 is predominantly expressed in the nucleus of TRAIL-resistant human tumor cell lines and has been shown to escape cell death and be transported to the nucleus via the importin (Imp)β1-mediated pathway. Based on this fact, suppression/inhibition of Impβ1 in a human tumor cell xenograft mouse model resulted in rejection of human tumor cells.
Furthermore, in order to identify regulatory molecules for nuclear expression of DR5, a human shRNA library was gene-transfected into TRAIL-resistant human tumor cell lines, and a cell population with significantly higher plasma membrane DR5 expression than control cells was enriched to narrow down the key molecules. As a result, SUMOylation of the DR5 molecule may be involved as one of the reasons why tumor cells acquire TRAIL resistance.

Academic Significance and Societal Importance of the Research Achievements

正常細胞には細胞死を誘導せず腫瘍細胞にのみ細胞死を誘導する、TRAIL分子のレセプターであるDR5分子は、試験管内だけでなくマウスの生体内でも、インポーチンβ1分子を抑制することでDR5の核内への移行を抑制して、生着したヒト腫瘍細胞に細胞死を誘導して腫瘍を拒絶できることがわかった。従って、TRAIL抵抗性の腫瘍細胞に対して、DR5の核内移行を抑制する薬物は、分子標的がん治療の一つになる可能性が考えられる。また、DR5の核内移行への関与が示唆された、DR5タンパク質のSUMO化についても、腫瘍細胞に対してそれをコントロールすることができれば、がん治療の分子標的になる可能性があるだろう。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (2 results)

All 2020 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Inhibition of Importin β1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-Resistant Tumor Cells2020

    • Author(s)
      Yuko Kojima, Takashi Nishina, Hiroyasu Nakano, Ko Okumura, Kazuyoshi Takeda
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 19-5 Issue: 5 Pages: 1123-1133

    • DOI

      10.1158/1535-7163.mct-19-0597

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Importin β1 inhibition augments anticancer effect of anti-DR5 agonistic antibody in TRAIL resistant tumor cells2019

    • Author(s)
      Yuko Kojima, Takashi Nishina, Hiroyasu Nakano, Ko Okumura, Kazuyoshi Takeda
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2025-01-30  

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