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.
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The critical dependency of ferroptosis on iron can be ascribed to the ability of iron to promote non-enzymatic lipid oxidation via lysosomal Fenton reactions.
“Alternatively, the critical dependency of ferroptosis on iron can also be ascribed to the ability of this heavy metal to promote non-enzymatic lipid oxidation via lysosomal Fenton reactions [538, 572, 576, 577].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [572]
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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
- 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
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Epidemiology › 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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