Molecular mechanisms regulating energy metabolism and stemness property

• Project/Area Number: 17K07160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Kobayashi Masahiko 金沢大学, がん進展制御研究所, 助教 (70285633)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: glioma / 膠芽腫 / オートファジー / 神経膠芽腫 / 癌

Outline of Final Research Achievements

Metabolism change plays a critical role in tumor progression and malignancy, but how regulation of metabolism contributes to cancer cells' responses to chemotherapeutics remains to be fully elucidated. In this study, we showed that compounds, which mobilize intracellular calcium, impair mitochondrial functions and reduce cellular ATP levels, were enhanced the glioma-suppressive efficacy by autophagy inhibition. Furthermore, using a patient-derived xenograft model, we demonstrated that chloroquine, a pharmacological autophagy inhibitor, dramatically enhanced the glioma-suppressive efficacy of compounds selected in this study. These results suggested that inhibition of autophagic metabolic regulation makes glioma cells susceptible to disturbance of calcium homeostasis. Our findings propose a novel therapeutic strategy in which calcium-mobilizing compounds are combined with autophagy inhibitors to treat glioma patients.

Academic Significance and Societal Importance of the Research Achievements

膠芽腫は、治療抵抗性の予後不良悪性疾患であり、未だ治癒に至る有効な治療法は開発されていない。本研究では、がん特有の代謝調節を標的とした膠芽腫に対する新たな治療法の探索を行い、カルシウムホメオスタシスを撹乱する化合物とオートファジー阻害の組み合わせが膠芽腫の抑制に効果的であることを示した。これまで、がんの抑制におけるオートファジーの効果は相反する報告があり曖昧であったが、本研究の結果はオートファジー抑制によって感受性が増加する標的経路を特定するものである。また、本研究の結果は、膠芽腫の新たな治療法を提案するものである。

Research Products

• [Journal Article] Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma (2019)
  • Author(s): Kitabayashi Tomohiro、Dong Yu、Furuta Takuya、Sabit Hemragul、Jiapaer Shabierjiang、Zhang Jiakang、Zhang Guangtao、Hayashi Yasuhiko、Kobayashi Masahiko、Domoto Takahiro、Minamoto Toshinari、Hirao Atsushi、Nakada Mitsutoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10049-10049
  • DOI: 10.1038/s41598-019-46454-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. (2018)
  • Author(s): Vu HT, Kobayashi M, Hegazy AM, Tadokoro Y, Ueno M, Kasahara A, Takase Y, Nomura N, Peng H, Ito C, Ino Y, Todo T, Nakada M, Hirao A
  • Journal Title: Cancer Science Volume: 109 Issue: 8 Pages: 2497-2508
  • DOI: 10.1111/cas.13695
  • Peer Reviewed / Open Access
• [Journal Article] Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells (2018)
  • Author(s): Hui Peng, Atsuo Kasada, Masaya Ueno, Takayuki Hoshii, Yuko Tadokoro, Naho Nomura, Chiaki Ito, Yusuke Takase, Ha Thi Vu, Masahiko Kobayashi, Bo Xiao, Paul F. Worley, Atsushi Hirao
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 1129-1135
  • DOI: 10.1016/j.bbrc.2017.11.140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug (2017)
  • Author(s): Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, Ino Y, Todo T, Teng L, Hirao A, Zhao SG, Nakada M
  • Journal Title: Oncotarget Volume: 8 Issue: 67 Pages: 111728-111741
  • DOI: 10.18632/oncotarget.22904
  • Peer Reviewed / Open Access
• [Presentation] Construction of a reporter system of undifferentiated cells to characterize patient-derived glioma-initiating cells (2019)
  • Author(s): 小林昌彦、平尾敦
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Identification of molecular targets in autophagy pathway to achieve efficient therapy of malignant gliomas (2019)
  • Author(s): Kobayashi M, Vu HT, Hegazy AM, Jing Y, Chen X, Tadokoro Y, Ueno M, Kasahara A, Hirao A
  • Organizer: The 14th international symposium of the institute network for biomedical sciences
  • Int'l Joint Research
• [Presentation] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas (2018)
  • Author(s): 小林昌彦、平尾敦
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Metabolic regulation of malignant phenotypes of glioma stem cells (2018)
  • Author(s): Kobayashi M, Vu HT, Yamada D, Hegazy AM, Hirao A
  • Organizer: The 1st NanoLSI International Symposium
  • Int'l Joint Research