Targeting of mitochondrial NEET for treatment of osteosarcoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16671
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Nara Medical University
• Principal Investigator: Kishi Shingo 奈良県立医科大学, 医学部, 助教 (50790341)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ミトコンドリア / ミトコンドリア小胞体係留分子 / 骨肉腫

Outline of Final Research Achievements

Cancer stem cells undergo mitochondrial-dominant metabolism and produce ATP while maintaining an optimal ROS level. We then suspect that mitochondria might posess a unique regulatory mechanism for that purpose. We focused on PDZD8, which is one of the endoplasmic reticulum-mitochondrial tethering molecules as a mitochondrial control mechanism. PDZD8 showed cancer-specific expression, and its knockdown showed disappearance of suppression of oxygen consumption, increased oxidative stress, increased cytotoxicity, and decreased stemness in stress conditions. These results suggest that the endoplasmic reticulum-mediated control system of mitochondrial ROS-ATP balance is involved in the metabolic phenotype of cancer stem cells, suggesting that PDZD8 is a new therapeutic target for cancer stem cells.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

がんにおける代謝の重要性は近年とくに注目されている。しかし、がんエネルギー代謝におけるミトコンドリア―小胞体係留分子に着目した研究はいまだに乏しい。本研究では、ミトコンドリア―小胞体係留分子であるミトコンドリアNEETおよびPDZD8のがん細胞における役割を解明し、これらを標的とする治療戦略に結びつく知見を得ることができた。とくに、骨肉腫のような治療的選択肢に乏しい悪性腫瘍に対する新規かつ有効な治療法の開発を可能にする知見が得られたことは、学術的にも社会的も大きな意義があったと考えられる。