Molecular Mechanisms behind Cancer Cells-specific Oxygen Homeostasis and Their Influence on Tumor Radioresistance

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293276
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Kyoto University
• Principal Investigator: Harada Hiroshi 京都大学, 放射線生物研究センター, 教授 (80362531)
• Co-Investigator(Kenkyū-buntansha): 吉村 通央 京都大学, 医学(系)研究科(研究院), 助教 (40597936) ; 小林 稔 京都大学, 医学(系)研究科(研究院), 研究員 (40644894)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 放射線治療 / がん / 治療抵抗性 / 酸素恒常性 / エネルギー代謝 / HIF-1 / 低酸素 / 微小環境

Outline of Final Research Achievements

We identified IDH3, UCHL1, and LY6E as novel activators of HIF-1. IDH3 was found to induce tumor angiogenesis by stabilizing HIF-1A and upregulating HIF-1A TAD activity. UCHL1 was confirmed to promote distant tumor metastasis by deubiquitinating and stabilizing HIF-1A protein. LY6E was revealed to induce tumor angiogenesis by facilitating the transcriptional initiation of HIF-1A gene. The UCHL1-HIF-1 axis was found to induce radioresistance of cancer cells by increasing intracellular levels of an antioxidant, GSH, in a glucose-6-phosphate dehydrogenase-dependent pentose phosphate pathway (PPP)-dependent manner.

Free Research Field

放射線腫瘍生物学