1. An essential role for functional lysosomes in ferroptosis of cancer cells
- Author
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Masaya Sasaki, Yuhei Yoshimoto, Toshinobu Suzuki, Masanobu Mori, Seiji Torii, Chisato Kubota, Ryosuke Shintoku, Toshiyuki Takeuchi, Ryoko Torii, Makoto Yaegashi, and Keiichi Yamada
- Subjects
0301 basic medicine ,Programmed cell death ,Aspartic Acid Proteases ,Iron ,Deferoxamine ,Biochemistry ,Piperazines ,03 medical and health sciences ,Cell Line, Tumor ,Lysosome ,Pepstatins ,medicine ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Cell Death ,biology ,Autophagy ,Cell Biology ,Cell biology ,Ferritin ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Transferrin ,Cancer cell ,biology.protein ,HT1080 ,Lysosomes ,Reactive Oxygen Species ,Intracellular - Abstract
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.
- Published
- 2016
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