Cited by 352Ferroptosis and cancer prognosisAutophagy in Disease and TherapyIron Metabolism and Disorders

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An essential role for functional lysosomes in ferroptosis of cancer cells

Torii, Seiji, Shintoku, Ryosuke, Kubota, Chisato, Yaegashi, Makoto, Torii, Ryoko, Sasaki, Masaya, Suzuki, Toshinobu, Mori, Masanobu, Yoshimoto, Yuhei, Takeuchi, Toshiyuki, Yamada, Keiichi·2016·Biochemical Journal

DOI 10.1042/bj20150658

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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.

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Authors: Torii, S., Shintoku, R., Kubota, C., Yaegashi, M., Torii, R., Sasaki, M., Suzuki, T., Mori, M., Yoshimoto, Y., Takeuchi, T., & Yamada, K.
Affiliations: Gunma University (JP)
Corresponding author: Torii, Seiji
Shintoku, Ryosuke
Kubota, Chisato
Yaegashi, Makoto
Torii, Ryoko
Takeuchi, Toshiyuki
ORCID: Torii, Seiji
Shintoku, Ryosuke
Torii, Ryoko
Mori, Masanobu
Yoshimoto, Yuhei
Takeuchi, Toshiyuki
Yamada, Keiichi
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2016-03-10
Volume: 473
Issue: 6
Pages: 769-777
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj20150658
OpenAlex: W2238799256
Cited by: 349
References: 39
Citations by year: 2026: 19 · 2025: 36 · 2024: 37 · 2023: 43 · 2022: 66 · 2021: 46 · 2020: 40 · 2019: 30 · 2018: 16 · 2017: 11 · 2016: 5
FWCI: 18.47
Type: journal article
Language: en
Open access: closed
Locations: Biochemical Journal (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science (24390050)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords: ferroptosis, lysosomes, lipid peroxidation, intracellular iron, ferritin degradation, autophagy, erastin, RSL3, fibrosarcoma, oncogenic Ras, cell death
MeSH terms: Deferoxamine, Humans, Iron, Lysosomes, Pepstatins, Piperazines, Cell Death, Reactive Oxygen Species, Cell Line, Tumor, Aspartic Acid Proteases

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An essential role for functional lysosomes in ferroptosis of cancer cells

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