细胞内
细胞生物学
程序性细胞死亡
自噬
溶酶体
癌细胞
HT1080型
GPX4
转铁蛋白受体
胞浆
癌症研究
生物
化学
细胞凋亡
细胞
线粒体
癌症
活性氧
生物化学
酶
遗传学
作者
Seiji Torii,Ryosuke Shintoku,Chisato Kubota,Makoto Yaegashi,Ryoko Torii,Masaya Sasaki,Toshinobu Suzuki,Miwako Mori,Yuhei Yoshimoto,Toshiyuki Takeuchi,Keiichi Yamada
摘要
Pharmacological challenges to oncogenic Ras-expressing cancer cells have shown a novel type of cell death, ferroptosis, which requires intracellular iron. In the present study, we assessed ferroptosis following treatment of human fibrosarcoma HT1080 cells with several inhibitors of lysosomal activity and found that they prevented cell death induced by the ferroptosis-inducing compounds erastin and RSL3. Fluorescent analyses with a reactive oxygen species (ROS) sensor revealed constitutive generation of ROS in lysosomes, and treatment with lysosome inhibitors decreased both lysosomal ROS and a ferroptotic cell-death-associated ROS burst. These inhibitors partially prevented intracellular iron provision by attenuating intracellular transport of transferrin or autophagic degradation of ferritin. Furthermore, analyses with a fluorescent sensor that detects oxidative changes in cell membranes revealed that formation of lipid ROS in perinuclear compartments probably represented an early event in ferroptosis. These results suggest that lysosomal activity is involved in lipid ROS-mediated ferroptotic cell death through regulation of cellular iron equilibria and ROS generation.
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