the development of novel prognostic marker and targeted therapy related to mitochondrial dynamics and calcium signaling in chemoresistant ovarian cancer

• Project/Area Number: 17K16840
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: University of Fukui
• Principal Investigator: Tsuyoshi Hideaki 福井大学, 学術研究院医学系部門(附属病院部), 助教 (90593864)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 抗癌剤抵抗性卵巣癌 / 細胞内カルシウム伝達 / ミトコンドリア分裂 / アポトーシス / 癌

Outline of Final Research Achievements

In the present study, we have investigated the mechanisms of chemoresistance in ovarian cancer (OVCA). We have shown that a calcium mobilizing agent, saikosaponin-d suppressed phospho-Drp1Ser637 content and CaMKI phosphorylation - which has also been reported to up-regulate Drp1 - leading to mitochondrial fission and subsequently apoptosis in chemoresistant OVCA cells. Extending from these in vitro findings, we have examined the clinical relevance and prognostic impact of Drp1, CaMKI and their phosphorylated forms in epithelial OVCA. Phospho-Drp1Ser637 emerged as an independent prognostic factor for progression-free survival which serves as the first report to explain the role of Drp1 and its related proteins in comprehensive patients’ cohort. These findings are promising and provide important insights into developing novel prognostic marker and targeted therapy in the patients with epithelial OVCA.

Academic Significance and Societal Importance of the Research Achievements

抗癌剤抵抗性卵巣癌における有効な治療戦略は未だに未解決のままである。本研究では、抗癌剤抵抗性獲得における細胞内カルシウム伝達・ミトコンドリア動態の役割を基礎的に解明し、これらを調節する薬剤を同定したことで、従来の抗癌剤とは異なる経路によって癌の細胞死を誘導する新規治療薬の開発へとつなぐことができる。更に臨床検体からこれらの機序に関連するタンパク発現を調査し、臨床所見及び経過との強い相関関係を証明したことで、癌の再発を予測する早期バイオマーカーの開発へとつなぐことができる。これら2つのアプローチから、予後不良の抗癌剤抵抗性卵巣癌患者に対する新規治療戦略の開発へとつながる可能性を示唆している。

Research Products

• [Journal Article] Prognostic Impact of Dynamin related protein 1 (Drp1) in Epithelial Ovarian Cancer (2020)
  • Author(s): Tsuyoshi H, Orisaka M, Fujita Y, Asare-Werehene M, Tsang BK, Yoshida Y
  • Journal Title: BMC Cancer Volume: -
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest. (2017)
  • Author(s): H.Tsuyoshi, VKW.Wong, Y.Han, M.Orisaka, Y.Yoshida, BK.Tsang
  • Journal Title: Oncotarget Volume: 8（59） Issue: 59 Pages: 99825-99840
  • DOI: 10.18632/oncotarget.21076
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 研究って・・・どうなの (2018)
  • Author(s): 津吉 秀昭
  • Organizer: 第10回 リサーチ・マッチング（研究者勧誘に係る説明会）
• [Presentation] Saikosaponin-d, a calcium mobilizing agent, sensitizeschemoresistant ovarian cancer cells to cisplatin-inducedapoptosis by facilitating mitochondrial fission and G2/M arrest. (2018)
  • Author(s): 津吉 秀昭
  • Organizer: 第9回2017年度優秀論文（2017.4～2018.3.31）発表会
• [Presentation] Saikosaponin-d sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest (2017)
  • Author(s): Hideaki Tsuyoshi, Makoto Orisaka, Yoshio Yoshida.
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] 抗癌剤抵抗性卵巣癌のカルシウム伝達とミトコンドリア動態に着目した治療戦略の開発 (2017)
  • Author(s): 津吉 秀昭
  • Organizer: 第4回 中日本産婦人科セミナー
• [Presentation] 抗癌剤抵抗性卵巣癌のカルシウム伝達とミトコンドリア動態に着目した治療戦略の開発 (2017)
  • Author(s): 津吉 秀昭
  • Organizer: 第4 回 新潟産婦人科シンポジウム
• [Presentation] 抗癌剤抵抗性卵巣癌のカルシウム伝達とミトコンドリア動態に着目した治療戦略の開発 (2017)
  • Author(s): 津吉 秀昭
  • Organizer: 第16回日本婦人科がん分子標的研究会