Cell death & disease, 2019-10, Vol.10 (10), p.755-12, Article 755
2019
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Details
- Autor(en) / Beteiligte
- Titel
- The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis
- Ist Teil von
- Cell death & disease, 2019-10, Vol.10 (10), p.755-12, Article 755
- Ort / Verlag
- England: Springer Nature B.V
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent lipid peroxidation and is implicated in several human pathologies, such as tissue ischemia, neurodegeneration, and cancer. Ferroptosis appears to be high cell-context dependent and the regulation of ferroptosis by physiological or pathological conditions are unclear. Here, we report that tumor-derived IDH1 mutation sensitizes cells to ferroptosis. Deletion of the mutant IDH1 allele in IDH1 heterozygous tumor cells or pharmacological inhibition of mutant IDH1 to produce the oncometabolite D-2-hydroxyglutarate (D-2-HG) confers resistance to erastin-induced ferroptosis. Conversely, ectopic expression of mutant IDH1 or treatment of cells with cell-permeable D-2-HG promotes the accumulation of lipid reactive oxygen species (ROS) and subsequently ferroptosis. Mechanistically, mutant IDH1 reduces the protein level of the glutathione peroxidase 4 (GPX4), a key enzyme in removing lipid ROS and ferroptosis, and promotes depletion of glutathione. Our results uncover a new role of mutant IDH1 and 2-HG in ferroptosis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-4889eISSN: 2041-4889DOI: 10.1038/s41419-019-1984-4Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6779886
- Format
- –
- Schlagworte
- Alleles, Apoptosis, Cell death, Cell Line, Tumor, Clonal deletion, Ectopic expression, Ferroptosis, Ferroptosis - drug effects, Ferroptosis - genetics, Gene deletion, Glutarates - metabolism, Glutathione peroxidase, Humans, Iron - metabolism, Ischemia, Ischemia - genetics, Ischemia - pathology, Isocitrate Dehydrogenase - genetics, Lipid peroxidation, Lipid Peroxidation - genetics, Lipids, Neoplasms - genetics, Neoplasms - metabolism, Neoplasms - pathology, Nerve Degeneration - genetics, Nerve Degeneration - pathology, Neurodegeneration, Piperazines - toxicity, Reactive oxygen species, Reactive Oxygen Species - metabolism, Tumor cells