The relationship between redox balance and drug resistance in uterine serous carcinoma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16827
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Yamagata University
• Principal Investigator: Obata Miyuki 山形大学, 医学部, 非常勤講師 (70613066)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 子宮体部漿液性癌 / スルファサラジン / レドックス機構 / フェロトーシス / JNK / 合成致死

Outline of Final Research Achievements

We investigated the effect of the xCT inhibitor sulfasalazine (SAS) on cytotoxicity in paclitaxel-sensitive and -resistant USC cell lines. We also examined the mechanism by which SAS induces ferroptotic cell death in paclitaxel-resistant cells. The results of proliferation assay showed that SAS promoted growth inhibition more effectively in paclitaxel-resistant than -sensitive cells, but did not enhance paclitaxel cytotoxicity in both USC cell lines. Immunoblotting analysis and the experiments conducted using ferroptosis inhibitors revealed SAS-mediated cell death was induced through ferroptosis—and not apoptosis—in paclitaxel-resistant cells. The synthetic lethal interaction between ROS accumulation and Ras effector JNK activation might be critical for enhancing the sensitivity to ferroptotic cell death mediated by xCT inhibitor SAS.

Free Research Field

婦人科腫瘍

Academic Significance and Societal Importance of the Research Achievements

子宮体部漿液性癌は再発率が高く、再発時は化学療法抵抗性となるため予後不良であるが、パクリタキセル耐性細胞株ではxCTを阻害することでフェロトーシスが誘導され強い殺細胞効果を示したことからxCT阻害剤が再発子宮体部漿液性癌患者に対する新たな治療法の一つとなる可能性が示唆された。