2023 Fiscal Year Final Research Report

Comprehensive analysis of glutathione-related molecular changes induced by inhibition of GGCT

Research Project

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Project/Area Number	21K09342
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56030:Urology-related
Research Institution	Shiga University of Medical Science
Principal Investigator	Kageyama Susumu 滋賀医科大学, 医学部, 教授 (50378452)
Co-Investigator(Kenkyū-buntansha)	富田圭司滋賀医科大学, 医学部, 非常勤講師 (30640148) 茶野徳宏滋賀医科大学, 医学部, 准教授 (40346028) 吉田哲也滋賀医科大学, 医学部, 助教 (60510310) 窪田成寿滋賀医科大学, 医学部, 助教 (80759118) 河内明宏滋賀医科大学, 医学部, 客員教授 (90240952) 草場拓人滋賀医科大学, 医学部, 助教 (90847211)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	γ-グルタミルシクロトランスフェラーゼ / グルタチオン / 抗癌療法
Outline of Final Research Achievements	(1) The expression patterns of the γ-glutamyl cycle component enzyme groups (GGT, GCLM, GCLC, GSS, and OPLAH) were examined by GGCT knockdown, and no significant changes were found. (2) A comparison of the expression of enzymes constituting the γ-glutamyl cycle and sensitivity to the GGCT inhibitor showed no specific correlation. (3) Knockdown of CHAC1, CHAC2, and GGACT, which are known as the GGCT family genes, showed similar inhibition of cancer cell proliferation as GGCT. However, these three genes showed growth inhibition in normal cells, suggesting that GGCT is still the best target molecule for cancer therapy. (4) In renal cancer cell lines, a decrease in intracellular glutathione was observed upon Pro-GA treatment. Furthermore, the rescue effect of NAC or exogenous glutathione was confirmed, suggesting that the mechanism of cell injury by GGCT inhibition is a decrease in intracellular glutathione followed by an increase in reactive oxygen species (ROS), leading to cell death.
Free Research Field	泌尿器腫瘍学
Academic Significance and Societal Importance of the Research Achievements	グルタチオン関連酵素からは、GGCT抗癌治療の予後予測バイオマーカーを同定することが出来なかったが、本研究により、GGCT抗癌作用の一端を明らかにすることが出来た。