ArticleOncotarget2017
CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 188 papers.
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Who cites it
188 citing papers in PubMed, 294 citations in OpenAlex.
- Circular RNAs in ferroptosis regulation and tumor progression of gynecological and breast cancers: molecular mechanisms and therapeutic potential.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Metformin Inhibits Ferroptotic Cell Death by Suppressing Cysteine Deprivation-Induced Mitochondrial Dysfunction.Pharmacology research & perspectives · 2026Article
- CHAC1-linked NRF2 protein expression participates in pancreatic islet protection by dextrorphan.iScience · 2026Article
- Article
- GSH-Related Enzymes GPx4, Chac1, and GSTs and Redox Regulation of Ferroptosis in Cancer.International journal of molecular sciences · 2026Review
- Flavonoid-mediated modulation of ferroptosis: therapeutic potential in gastrointestinal cancers.Journal of advanced research · 2026Review
- Dissecting Complex Interactions Between Ferroptosis and the Proteasome.bioRxiv : the preprint server for biology · 2026Article
- Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.Cell reports · 2026Article
- PEDV infection induces ferroptosis in Vero cells via an ACSL4-mediated lipid peroxidation pathway.Archives of virology · 2026Article
- Cytoprotective Mechanism of Necrox-5 Against Toxicity Induced by Experimental Ferroptosis Instigators and the Pesticide Propargite.International journal of molecular sciences · 2026Article
- BACH1-CHAC1-Glutathione Axis Aggravates Myocardial Ischemia-Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress.Antioxidants (Basel, Switzerland) · 2026Article
- The Landscape of Ferroptosis-Related Gene Signatures as Molecular Stratification in Triple-Negative Breast Cancer.Diagnostics (Basel, Switzerland) · 2026Article
- Ferroptosis in liver diseases: molecular mechanisms, biomarker potential, and clinical translation.Frontiers in cell and developmental biology · 2026Review
- Ferroptosis-associated myeloid cell heterogeneity and inflammatory amplification following spinal cord injury.Frontiers in immunology · 2026Article
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- Repurposing loratadine to induce ferroptosis and overcome multidrug resistance: preclinical evidence in KB-V-1 cells.Frontiers in oncology · 2026Article
- Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.Science advances · 2025Article
- Metabolic Regulation of Ferroptosis in Breast Cancer.International journal of molecular sciences · 2025Review
- Protein S-glutathionylation confers cellular resistance to ferroptosis induced by glutathione depletion.Redox biology · 2025Article
- Nanotherapeutics induced redox resetting of oxidative and nitrosative stress: targeting glutathione-depletion in cancer.Nanomedicine (London, England) · 2025Review
128 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells. Moreover, cystine starvation induced mitochondrial fragmentation, dysfunction, and ROS production. A mitochondrial ROS scavenger, Necrox-5, can prevent cystine-starvation-induced cell death. In addition, cystine starvation was found to activate GCN2, but not PERK, to increase the phosphorylation of eIF2α at serine 51, the protein expression of ATF4, and the expression of ATF4 target genes such as CHAC1, which might be downstream of the RIP1/RIP3-MLKL pathway and contribute to cystine-starvation-induced cell death. Knockdown of CHAC1 rescued the cystine-starvation-induced reduction in glutathione (GSH) levels and cell death. Furthermore, N-acetyl-cysteine (NAC), Trolox, and Nec-1 significantly prevented the cystine-starvation-induced increase in intracellular ROS levels, mitochondrial fragmentation and cell death. In summary, these results suggest that CHAC1 degradation of GSH enhances cystine-starvation-induced necroptosis and ferroptosis through the activated GCN2-eIF2α-ATF4 pathway in TNBC cells. Our findings improve our understanding of the mechanism underlying cystine-starvation-induced TNBC cell death.
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