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MTflEcad I80 and MTflEcad DI150 cells, long-term treated murine derived breast cancer cell lines with H2O2

ABSTRACT: Background: Epithelial-mesenchymal transition (EMT) has been implicated in metastasis, drug resistance, survival under stress and also conferring stem cell-like traits to cancer cells. We have aimed at exploring the crosstalk between ROS and an EMT induced by TGFb in breast cancer cells. Methods: We observed that cells exposed to TGFb displayed a decrease of ROS levels. To identify the antioxidant pathways activated during EMT, we investigated the effect of long-term oxidative stress, for example by H2O2 (80 µM and 150 µM), on MTflECad epithelial cells derived from the MMTV-Neu mouse model. Results: We show that long-term treated MTflEcad epithelical cells with H2O2 display both higher migratory capability and tumorigenicity. Furthermore, we identified an activation of the Nrf2 transcription factor, master regulator of the antioxidant response, in H2O2-resistant cells, as well as in TGFb-induced mesenchymal cells. Conclusion: In this study we report the criticial role of the Nrf2-mediated glutathione metabolism in the protection of metastatic breast cancer cells from ferroptosis. Therapeutic targeting of antioxidant pathways may thus be beneficial for patients with metastatic disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE187476 | GEO | 2022/10/15

REPOSITORIES: GEO

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Py2T C40 and Py2T I60 cells, long-term treated murine derived breast cancer cell lines with H2O2

Project description:Background: Epithelial-mesenchymal transition (EMT) has been implicated in metastasis, drug resistance, survival under stress and also conferring stem cell-like traits to cancer cells. We have aimed at exploring the crosstalk between ROS and an EMT induced by TGFb in breast cancer cells. Methods: We observed that cells exposed to TGFb displayed a decrease of ROS levels. To identify the antioxidant pathways activated during EMT, we investigated the effect of long-term oxidative stress, for example by H2O2 (40 µM and 60 µM), on Py2T epithelial cells derived from the MMTV-PyMT mouse model. Results: We show that long-term treated Py2T epithelical cells with H2O2 display both higher migratory capability and tumorigenicity. Furthermore, we identified an activation of the Nrf2 transcription factor, master regulator of the antioxidant response, in H2O2-resistant cells, as well as in TGFb-induced mesenchymal cells. Conclusion: In this study we report the criticial role of the Nrf2-mediated glutathione metabolism in the protection of metastatic breast cancer cells from ferroptosis. Therapeutic targeting of antioxidant pathways may thus be beneficial for patients with metastatic disease.

2022-10-15 | GSE187364 | GEO

RNAi-mediated ablation of Nrf2 in PyMT-1099 LT, Py2T LT and MT∆Ecad mesenchymal breast cancer cells

Project description:Background: Epithelial-mesenchymal transition (EMT) has been implicated in metastasis, drug resistance, survival under stress and also conferring stem cell-like traits to cancer cells. We have aimed at exploring the crosstalk between ROS and an EMT induced by TGFb in breast cancer cells. Methods: We observed that cells exposed to TGFb displayed a decrease of ROS levels. Furthermore, we identified an activation of the Nrf2 transcription factor, master regulator of the antioxidant response in TGFb-induced mesenchymal cells. In order to know the effect of Nrf2 ablation in epithelial and mesenchymal cells, RNAi-mediated ablation for Nrf2 was performed. Results: RNAi-mediated ablation of Nrf2 led to mesenchymal cancer cell death due to ferroptosis, an iron- and oxidative stress-dependent cell death. Moreover, analysis revealed that several glutathione pathway genes were specifically regulated by Nrf2, suggesting a role of glutathione-related pathways in mesenchymal cell survival. Conclusion: In this study we report the criticial role of the Nrf2-mediated glutathione metabolism in the protection of metastatic breast cancer cells from ferroptosis. Therapeutic targeting of antioxidant pathways may thus be beneficial for patients with metastatic disease.

2022-10-15 | GSE187478 | GEO

Sedanolide ameliorates hydrogen peroxide-induced apoptotic cell death via activation of KEAP1-NRF2 pathway

Project description:Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H2O2)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H2O2-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H2O2. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H2O2-induced cell death by preventing the decrease of the mitochondrial membrane potential and the increase of caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Keich-like ECH-associated protein 1 (KEAP1)–NRF2 pathway.

2023-11-29 | GSE245428 | GEO

Pereira2020 - NRF2–p53 integrated-systems model of oxidative stress

Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2. The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).

2021-10-29 | MODEL2110270001 | BioModels

Deficient Pink1 Retrograde Mitochondrial-Nrf2 Signaling Induces EMT That Is Mitigated By A Mitochondria-tropic ROS Reducing Dendrimer

Project description:Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without effective treatment for early, dry disease. Retinal pigment epithelial (RPE) cell degeneration is a cardinal feature of dry AMD. Given the reliance of photoreceptors on the RPE for maintaining health and vision, rejuvenating dysfunctional RPE is a logical treatment strategy. Here, the interplay between two cytoprotective pathways, Pink1 mediated mitophagy and the Nrf2 stress-response, was studied in human AMD tissue samples, RPE cells, and relevant mouse models. Pink1 immunolabeling was decreased in the RPE of early AMD eyes. The RPE from Pink1-/- mice and Pink1 deficient cultured human RPE cells displayed impaired mitophagy, decreased aerobic respiration, and increased mitochondrial reactive oxygen species (ROS) generation, and coincidently, developed morphological, molecular, and functional features of epithelial-mesenchymal transition (EMT). This change was triggered by novel retrograde mitochondrial to nuclear signaling that was initiated by mitochondrial ROS, which activated Nrf2 to induce TXNRD1, PI3K/AKT, and canonical EMT transcription factors Zeb1 and Snail. Nrf2 signaling was pivotal since its deficiency prevented EMT and increased cell death. A dendrimer containing N-acetyl cysteine that is tropic for the RPE and contains the mitochondrial targeting ligand Triphenyl phosphinium abrogates EMT in human RPE cells in vitro and in Pink1-/- mice. This study describes a novel interdependency of mitophagy and the Nrf2 antioxidant response in determining cell fate and introduces an RPE and mitochondrial specific ROS reducing dendrimer that can rescue RPE cells in EMT, a change recognized in early AMD.

2022-01-01 | GSE186751 | GEO

Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

Project description:Mitochondrial dysfunction is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed mitochondrial homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of NRF2 antioxidant pathway as a driver mechanism for mitochondrial dysfunction and ADPKD progression. Using a quantitative proteomic approach, we find that NRF2 antioxidant pathway is suppressed in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the increased ROS levels inversely correlates with decreased NRF2 expression and positively correlates with disease severity. Genetic deletion of NRF2 increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of NRF2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, NRF2 activates its antioxidant target genes mainly through remodeling enhancer landscapes. The activation domain of NRF2 forms phase-separated condensates with MED16, a Mediator complex subunit in vitro, and NRF2 is required for optimal Mediator recruitment to target genomic sites in vivo. Taken together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase-separation mechanism, and that activation of NRF2 represents a promising strategy for restoring mitochondrial homeostasis and combatting ADPKD.

2021-12-12 | PXD016312 | Pride

Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [RNA-seq]

Project description:Oxidative stress is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed redox homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of Nrf2 antioxidant pathway as a driver mechanism for oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemistry analyses, we find that Nrf2 antioxidant pathway is suppressed due to increased degradation of Nrf2 protein in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the ROS levels inversely correlates with Nrf2 abundance and positively correlates with disease severity. Genetic deletion of Nrf2 further increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of Nrf2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, pharmacological induction of Nrf2 remodels enhancer landscapes and activates Nrf2-bound enhancer-associated genes in ADPKD cells. The activation domain of Nrf2 forms phase-separated condensates with Mediator subunit MED16 in vitro, and Nrf2 is required for optimal Mediator recruitment to target genomic loci in vivo. Taken together, these findings indicate that Nrf2 remodels enhancer landscapes and activates its target genes through a phase-separation mechanism, and that activation of Nrf2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.

2021-01-26 | GSE141740 | GEO

Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-seq]

2021-01-26 | GSE141739 | GEO

Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis

Project description:Outcomes for metastatic bone sarcomas, Ewing sarcoma and osteosarcoma, are dismal and remain unchanged for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. To explore this in sarcomas, we screened libraries of approved compounds for agents sensitizing sarcoma cells to oxidative stress. This identified the class I HDAC inhibitor MS-275 as enhancing sensitivity to reactive oxygen species (ROS). Mechanistically, MS-275 inhibits YB-1 deacetylation, decreasing physical binding between YB-1 and the 5UTR of NFE2L2, thereby non-transcriptionally reducing translation and expression of the master antioxidant factor, NRF2, which reduces cellular ROS. Indeed, global acetylomics revealed that MS-275 promotes rapid acetylation of the YB-1 RNA binding protein at lysine-81, blocking RNA binding and translational activation of NFE2L2, encoding NRF2, as well as known YB-1 mRNA targets, HIF1A and the stress granule nucleator, G3BP1. MS-275 dramatically reduced sarcoma metastasis in vivo, but an MS-275-resistant YB-1 K81-to-alanine (K81A) mutant restored metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS-275 treated mice. These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity.

2019-10-28 | PXD014827 | Pride

Del Nido Cardioplegia or Potassium Induces Nrf2 and Protects Cardiomyocytes Against Oxidative Stress

Project description:Open heart surgery is often an unavoidable procedure for treatment of coronary artery disease. The procedure associated reperfusion injury affects postoperative cardiac performance and long-term outcome. We addressed here whether cardioplegia essential for cardiopulmonary bypass surgery activates Nrf2, a transcription factor regulating the expression of antioxidant and detoxification genes. With commonly used cardioplegic solutions, High K+, Low K+, Del Nido (DN), histidine-tryptophan-ketoglutarate (HTK) and Celsior, we found that DN causes an increase of Nrf2 protein in AC16 human cardiomyocytes. Tracing the ingredients in DN led to the discovery of KCl at the concentration above 5 mM capable of Nrf2 protein induction. The Antioxidant Response Element luciferase reporter assay confirmed Nrf2 activation by DN or KCl. Transcriptomic profiling using RNA-seq revealed that oxidation-reduction as a main gene ontology group affected by KCl. KCl indeed elevated the expression of classical Nrf2 downstream targets, including TXNRD1, AKR1C, AKR1B1, SRXN1 and G6PD. DN or KCl induced Nrf2 elevation is Ca2+ concentration dependent. We found that KCl extended the half-life of Nrf2 from 17.8 to 25.1 mins, and decreased Nrf2 protein ubiquitination. Knocking out Keap1 blocked Nrf2 induction by K+. Nrf2 induction by DN or KCl protected against ROS generation or loss of viability by H2O2. Our data support that high K+ concentration in DN cardioplegic solution can induce Nrf2 protein, which in turn mediates protection of cardiomyocytes

2023-01-01 | GSE221058 | GEO

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