ArticleMolecular and cellular biochemistry2015
Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells.
Article in Molecular and cellular biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 53 citations in OpenAlex.
- Nrf2 and STAT3 Pathways in Protecting Against Methylmercury-Induced Oxidative Stress in Hypothalamic Neuronal GT1-7 Cells.Neurochemical research · 2026Article
- DKK1 Promotes Cisplatin Resistance in Oral Squamous Cell Carcinoma via SLC3A2-Dependent Ferroptosis Suppression.Cancer reports (Hoboken, N.J.) · 2026Article
- Sympathetic signaling activation alleviated acute respiratory distress syndrome via the HDC/SLC7A11 axis in lipopolysaccharide-induced macrophages.Cell death discovery · 2026Article
- Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.Cell death & disease · 2025Article
- TSLP mitigates post-infarction myocardial remodeling by promoting eosinophil recruitment and inhibiting JAK1-STAT5-mediated ferroptosis.Apoptosis : an international journal on programmed cell death · 2025Article
- Emerging Links Between Ferroptosis and Neurodegeneration: Implications for Disease Mechanisms and Nutraceutical Interventions.Food science & nutrition · 2025Review
- Ferroptosis enhances the therapeutic potential of oncolytic adenoviruses KD01 against cancer.Cancer gene therapy · 2025Article
- Regulation of Ferroptosis in Cancer and Immune Cells.Immune network · 2025Review
- Crosstalk between ferroptosis and innate immune in diabetic kidney disease: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- STAT3 Regulates the Redox Profile in MDA-MB-231 Breast Cancer Cells.Cell biochemistry and biophysics · 2024Article
- Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors.Antioxidants (Basel, Switzerland) · 2024Review
- Inhibition of LSD1 induces ferroptosis through the ATF4-xCT pathway and shows enhanced anti-tumor effects with ferroptosis inducers in NSCLC.Cell death & disease · 2023Article
- The crosstalk of CD8+ T cells and ferroptosis in cancer.Frontiers in immunology · 2023Review
- Recent progress in ferroptosis: inducers and inhibitors.Cell death discovery · 2022Review
- The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT-20 cells in vitro.FEBS letters · 2022Article
- C8orf76 Modulates Ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11.Cancers · 2022Article
- IFNγ enhances ferroptosis by increasing JAK‑STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma.Oncology reports · 2022Article
- Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis.Nature communications · 2022Article
- Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells.Cancer cell international · 2021Review
- System XcInvestigational new drugs · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
System Xc- is a cystine/glutamate antiporter that contributes to the maintenance of cellular redox balance. The human xCT (SLC7A11) gene encodes the functional subunit of system Xc-. Transcription factors regulating antioxidant defense mechanisms including system Xc- are of therapeutic interest, especially given that aggressive breast cancer cells exhibit increased system Xc- function. This investigation provides evidence that xCT expression is regulated by STAT3 and/or STAT5A, functionally affecting the antiporter in human breast cancer cells. Computationally analyzing two kilobase pairs of the xCT promoter/5' flanking region identified a distal gamma-activated site (GAS) motif, with truncations significantly increasing luciferase reporter activity. Similar transcriptional increases were obtained after treating cells transiently transfected with the full-length xCT promoter construct with STAT3/5 pharmacological inhibitors. Knock-down of STAT3 or STAT5A with siRNAs produced similar results. However, GAS site mutation significantly reduced xCT transcriptional activity, suggesting that STATs may interact with other transcription factors at more proximal promoter sites. STAT3 and STAT5A were bound to the xCT promoter in MDA-MB-231 cells, and binding was disrupted by pre-treatment with STAT inhibitors. Pharmacologically suppressing STAT3/5 activation significantly increased xCT mRNA and protein levels, as well as cystine uptake, glutamate release, and total levels of intracellular glutathione. Our data suggest that STAT proteins negatively regulate basal xCT expression. Blocking STAT3/5-mediated signaling induces an adaptive, compensatory mechanism to protect breast cancer cells from stress, including reactive oxygen species, by up-regulating xCT expression and the function of system Xc-. We propose that targeting system Xc- together with STAT3/5 inhibitors may heighten therapeutic anti-cancer effects.
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