Pyrimidine biosynthesis and energy metabolism in cancer microenvironment

2015 Fiscal Year Final Research Report

• Project/Area Number: 26870119
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bioorganic chemistry; Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: INAOKA KEN DANIEL 東京大学, 医学(系)研究科(研究院), 助教 (10623803)
• Co-Investigator(Renkei-kenkyūsha): KITA Kiyoshi 東京大学, 大学院医学系研究科, 教授 (90134444) ; HARADA Shigeharu 京都工芸繊維大学, 大学院工芸科学研究科, 教授 (80156504) ; SAIMOTO Hiroyuki 鳥取大学, 大学院工学系研究科, 教授 (20186977) ; HONMA Teruki 国立研究開発法人理化学研究所, ライフサイエンス技術基盤研究センター, チームリーダー (10466039)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 癌微小環境 / フマル酸呼吸 / ピリミジン生合成経路 / 新規薬剤標的 / ケミカルバイオロジー

Outline of Final Research Achievements

Pyrimidine are building blocks of DNA/RNA and essential to sustain life. Human cells obtain pyrimidine bases from either salvage or de novo biosynthesis pathways, which are completely dependent on pyrimidine precursors and oxygen, respectively. Both nutrients are provided by blood and the molecular mechanism of both pathways are well studied. Solid tumors are known to be hypovascularized making the provision of those nutrients extremely low (tumor microenvironment). Since the growth is not affected, those type of cancer cells may obtain pyrimidines by unknown mechanism. The present study aimed to identify the mechanism of pyrimidine acquisition in tumor microenvironment by biochemical, structural biology and reverse chemical biology approaches. As the main result, we have identified a novel mechanism involving mitochondria, which allows the pyrimidines de novo biosynthesis even in the absence of oxygen and can be explored for development of new drugs for cancer chemotherapy.

Free Research Field

生化学