title: An essential role for functional lysosomes in ferroptosis of cancer cells.
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.
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan storii@gunma-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Torii
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi 371-8512, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Shintoku
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Kubota
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yaegashi
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Torii
authors.affiliation: Department of Environmental Engineering Science, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Environmental Engineering Science, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Environmental Engineering Science, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi 371-8512, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Yoshimoto
authors.affiliation: Secretion Biology Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Chemistry and Chemical Biology, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008247:Lysosomes / Q000502:physiology*; D010436:Pepstatins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017382:Reactive Oxygen Species
chemical_list: D010436:Pepstatins; D010879:Piperazines; D017382:Reactive Oxygen Species; C477224:erastin; C014247:pepstatyl-arginine methyl ester; D007501:Iron; D057055:Aspartic Acid Proteases; D003676:Deferoxamine
keywords: Ras; autophagy; iron; necrosis; oxidative stress