Molecular mechanisms regulating energy metabolism and stemness property

2019 Fiscal Year Final Research Report

• 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
• Keywords: glioma

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.

Free Research Field

腫瘍生物学

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。