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

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07648
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Juntendo 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
• Keywords: Tumor cells / Cell deth / DR5 / Localization / Nucleus / Intracellular transport / Cancer therapy / SUMOylation

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.

Free Research Field

腫瘍生物学

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。