Development of novel therapeutic strategies based on metabolomics analysis of uterine serous carcinoma

• Project/Area Number: 15K10699
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Yamagata University
• Principal Investigator: Nagase Satoru 山形大学, 医学部, 教授 (00292326)
• Co-Investigator(Kenkyū-buntansha): 鈴木 史彦 東北大学, 医学系研究科, 助教 (20400343) ; 太田 剛 山形大学, 医学部, 講師 (50375341) ; 清野 学 山形大学, 医学部, 助教 (40594320)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 子宮体部漿液性癌 / メタボローム解析 / パクリタキセル耐性 / スルファサラジン / フェロトーシス / 子宮体部漿液性腺癌 / 抗がん剤耐性 / パクリタキセル

Outline of Final Research Achievements

First, we examined metabolomic profile in USC cells by analysis using a capillary electrophoresis CE-MS/MS system. The concentration of GSH, Glucose-6-phosphate and ribose-5-phasphate in the PTX-1 cells was higher than that of USPC-1 cells. Next, we investigated the effect of the xCT inhibitor sulfasalazine (SAS) on cytotoxicity in paclitaxel-sensitive and -resistant USC cell lines. The results of proliferation and cell-death assays showed that SAS enhanced the efficacy of paclitaxel in both paclitaxel-sensitive and -resistant cell lines. Immunoblotting analysis and experiments conducted using ferroptosis inhibitors revealed that SAS-mediated cell death was induced through ferroptosis, and not apoptosis, in paclitaxel-resistant cells. Collectively, our findings indicate that xCT inhibition can overcome resistance to paclitaxel, and could thus represent a candidate novel treatment for patients with recurrent chemotherapy-resistant USC.

Research Products

• [Journal Article] GSKJ4, A Selective Jumonji H3K27 Demethylase Inhibitor, Effectively Targets Ovarian Cancer Stem Cells. (2015)
  • Author(s): Sakaki H, Okada M, Kuramoto K, Takeda H, Watarai H, Suzuki S, Seino S, Seino M, Ohta T, Nagase S, Kurachi H, Kitanaka C.
  • Journal Title: Anticancer Res Volume: 35 Pages: 6607-6614
  • Peer Reviewed
• [Presentation] Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel. (2017)
  • Author(s): Seino M, Ohta T, Sugiyama A, Sakaki H, Sudo T, Nagase S.
  • Organizer: The 5th Biennial Meeting of Asian Society of Gynecologic Oncology
  • Int'l Joint Research
• [Presentation] 子宮体部漿液性癌のタキサン耐性獲得に関するメタボローム解析 (2017)
  • Author(s): 清野 学,太田 剛,杉山晶子,榊 宏諭,須藤 毅,永瀬 智.
  • Organizer: 第69回日本産科婦人科学会
• [Presentation] 子宮体部漿液性腺癌細胞株におけるスルファサラジンによるパクリタキセル抵抗性解除機構に関する検討 (2017)
  • Author(s): 杉山晶子,太田 剛,榊 宏諭,清野 学,須藤 毅,永瀬 智.
  • Organizer: 第69回日本産科婦人科学会