Targeting the Ubiquitin Proteasome Pathway as a Novel Therapeutic Strategy for Advanced Renal Cell Carcinoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07736
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kagoshima University
• Principal Investigator: YOSHINO Hirofumi 鹿児島大学, 医歯学域医学系, 講師 (90642611)
• Co-Investigator(Kenkyū-buntansha): 榎田 英樹 鹿児島大学, 医歯学域医学系, 教授 (80347103)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 腎細胞癌

Outline of Final Research Achievements

Disulfiram is a therapeutic drug for alcoholism, and the antitumor effect of disulfiram via NPL4 has recently been reported. NPL4 is a protein involved in the ubiquitin-proteasome system, and when inhibited by disulfiram, cells are unable to degrade the bad protein, leading to cell death. However, there are few reports related to disulfiram and NPL4 in renal cell carcinoma. Therefore, the purpose of this study is to explore the possibility of targeting NPL4 by disulfiram in renal cell carcinoma, to elucidate the cancer signaling pathways involved in these pathways, and to provide basic data for new therapeutic strategies.

Free Research Field

泌尿器癌

Academic Significance and Societal Importance of the Research Achievements

研究成果で、腎癌コホートにおいてNPL4高発現群は低発現群と比べて全生存期間が有意に低下していたことを示し、腎癌細胞株においてNPL4をsi-RNAやジスルフィラムで阻害すると、対照細胞と比べアポトーシス誘導を介した増殖能の有意な低下を認めた。また、増殖アッセイ、Xenograftアッセイにおいて、ジスルフィラム単独の腫瘍抑制効果とスニチニブとの併用効果を確認した。更に、腫瘍片を用いたプロテオミクス解析を行い、PSAT1やAKR1B1といった遺伝子の発現がジスルフィラム投与サンプルにおいて低下し、スニチニブとの併用サンプルにおいては更に低下していることを確認し、これらの成果を論文化した。