An essential role for functional lysosomes in ferroptosis of cancer cells

Author:

Torii Seiji1,Shintoku Ryosuke12,Kubota Chisato1,Yaegashi Makoto1,Torii Ryoko1,Sasaki Masaya3,Suzuki Toshinobu3,Mori Masanobu3,Yoshimoto Yuhei2,Takeuchi Toshiyuki1,Yamada Keiichi4

Affiliation:

1. Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan

2. Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi 371-8512, Japan

3. Department of Environmental Engineering Science, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan

4. Department of Chemistry and Chemical Biology, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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