Is ROS-sensing BAG-1/ATF4-system a regulatory system for ferroptosis?

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06630
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: Kuge Shusuke 東北医科薬科大学, 薬学部, 教授 (50186376)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: BAG-1 / フェロトーシス / シスチントランスポーター / ヘムオキシゲナーゼー１ / がん細胞 / SLC7A11 / Ferroptosis / P53

Outline of Final Research Achievements

BAG-1 is essential for mouse development, and its importance has been shown, such as the fact that high expression leads to resistance to anticancer drug treatment. In this study, we created new BAG-1 genetically modified mice and analyzed their properties. Contrary to previous reports, we found that the BAG-1 protein is not essential for mouse development and survival, but BAG-1-deficient cells are sensitive to oxidative stress caused by glutathione depletion. Furthermore, when human cancer cells were deficient in BAG-1, they were found to become sensitive to ferroptosis due to the control of heme oxygenase-1 expression. These results suggest that BAG-1 functions as a factor that controls oxidative stress sensitivity and ferroptosis through transcriptional regulation.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

これまでBag-1はマウス発生に必須な遺伝子として示されていた。本研究において新たに作製したBag-1欠失マウスは正常であるが、Bag-1欠失細胞は酸化ストレスの恒常性維持に寄与することを初めて示した。また、BAG-1の酸化ストレスとフェロトーシスの制御機構を示した。この知見はBAG-1による癌細胞の生存戦略の理解につながり、今後抗がん剤耐性癌細胞のBAG-1を阻害することで、BAG-1により抑制されるフェロトーシスを誘導する方法の有効性を示唆する知見を得た。BAG-1を負に制御できれば抗がん剤耐性化の回避など治療の選択肢を広げることができる。