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Estrogen-related receptors are targetable ROS sensors

ABSTRACT: Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Herein, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRα downregulation restricts glutamine entry into the TCA cycle while ERRγ upregulation promotes glutamine-driven glutathione production. Notably, we identify increased ERRγ expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERRγ with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERRγ inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role. In this study, ERRγ ChIP-seq analysis was performed under normal conditions in the breast cancer cell line BT-474.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144224 | GEO | 2020/02/07

REPOSITORIES: GEO

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Expression of Heterologous OsDHAR Gene Improves Glutathione (GSH)-Dependent Antioxidant System and Maintenance of Cellular Redox Status in Synechococcus elongatus PCC 7942

Project description:An excess of reactive oxygen species (ROS) can cause severe oxidative damage to cellular components in photosynthetic cells. Antioxidant systems, such as the ascorbate-glutathione cycle, regulate redox status in cells to guard against such damage. Dehydroascorbate reductase (DHAR, EC 1.8.5.1) catalyzes the glutathione-dependent reduction of oxidized ascorbate (dehydroascorbate) and contains a redox active site and glutathione binding-site. The DHAR gene is important in biological and abiotic stress responses involving reduction of the oxidative damage caused by ROS. In this study, a transgenic microalgae (TA) strain was constructed by cloning the Oryza sativa L. japonica DHAR (OsDHAR) gene controlled by an isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible promoter (Ptrc) into the Synechococcus elongatus PCC 7942 strain of cyanobacteria to study the functional activities of OsDHAR under oxidative stress caused by hydrogen peroxide exposure. OsDHAR expression increased the growth of S. elongatus PCC 7942 under oxidative stress by reducing the levels of hydroperoxides and malondialdehyde (MDA) and mitigating the loss of chlorophyll. DHAR and glutathione S-transferase activity were higher than in the wild-type (WT) strain. Additionally, overexpression of OsDHAR in S. elongatus PCC 7942 greatly increased the glutathione (GSH)/glutathione disulfide (GSSG) ratio compared to ascorbic acid (AsA)/dehydroascorbate (DHA) ratio in the presence or absence of hydrogen peroxide. These results strongly suggest that DHAR attenuates deleterious oxidative effects via the glutathione (GSH)-dependent antioxidant system in cyanobacterial cells. The expression of heterologous OsDHAR in S. elongatus PCC 7942 protected cells from oxidative damage through a GSH-dependent antioxidant system via GSH-dependent reactions at the redox active site and GSH binding site residues during oxidative stress.

2019-11-25 | GSE140121 | GEO

RNA sequencing of WT and ERRαγAd-/- brown adipose tissue treated with CL316,243

Project description:Adrenergic stimulation of brown adipose tissue (BAT) activates thermogenesis, by uncoupling oxidative phosphorylation and enabling high rates of substrate oxidation. Moreover, adrenergic stimulation signals to the nucleus, inducing gene expression changes that increase BAT thermogenic and oxidative capacity. The purpose of this study was to determine the role of two orphan nuclear receptors, ERRα and ERRγ, in adipose tissue function in response to adrenergic stimulation. Here we identify ERRα and ERRγ as collectively critical effectors of the adrenergic induced transcriptional program in BAT. Mice lacking adipose ERRs (ERRαγAd-/-) have diminished oxidative and thermogenic capacity, and become rapidly hypothermic when exposed to cold. Notably, the ability of the β3-adrenergic agonist CL316,243 to expand BAT oxidative and thermogenic capacity, increase energy expenditure, promote weight loss, and improve glucose tolerance is lost in ERRαγAd-/-. At the transcriptional level, RNA sequencing experiments show that the bulk of the response of BAT to CL316,243 (>80% of CL316,243-induced genes) relies on ERRs. These findings establish ERRα and ERRγ as essential BAT regulators that act coordinately to relay adrenergic signals and expand the capacity for thermogenesis and energy expenditure.

2018-03-19 | GSE104285 | GEO

RNAseq transcriptome analysis of Streptococcus pyogenes HKU16 and an isogenic gshT mutant. Manuscript title: Streptococcus pyogenes hijacks host glutathione for growth and innate immune evasion

Project description:The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus, GAS). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione is the major host antioxidant molecule while GAS is glutathione-auxotrophic. Here we report the molecular characterization of the ABC transporter substrate binding protein GshT in the GAS glutathione salvage pathway. We demonstrate that glutathione uptake is critical for aerobic growth of GAS and that impaired import of glutathione induces oxidative stress that triggers enhanced production of the reducing equivalent NADPH. Our results highlight the interrelationship between glutathione assimilation, carbohydrate metabolism, virulence factor production and innate immune evasion. Together, these findings suggest an adaptive strategy employed by extracellular bacterial pathogens to exploit host glutathione stores for their own benefit.

2022-04-04 | GSE198061 | 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

KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia

Project description:High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances in the use of tyrosine kinase inhibitors and chimeric- antigen-receptor engineered T cells. Lymphoblastic-leukemia precursors are highly sensitive to oxidative stress. KLF5 is a member of the Krüppel-like family of transcription factors. KLF5 expression is repressed in B-ALL, including BCR-ABL1+ B-ALL. Here, we demonstrate that forced expression of KLF5 in B-ALL cells bypasses imatinib resistance not associated with mutations of BCR-ABL. Expression of Klf5 impaired leukemogenic activity of BCR-ABL1+ B-cell precursors in vitro and in vivo. The complete genetic loss of Klf5 reduced oxidative stress, increased regeneration of reduced glutathione and decreased apoptosis of leukemic precursors. Klf5 regulation of glutathione levels was mediated by its regulation of glutathione-S-transferase Mu 1 (Gstm1), an important regulator of glutathione-mediated detoxification and protein glutathionylation. Expression of Klf5 or the direct Klf5 target gene Gstm1 inhibited clonogenic activity of Klf5∆/∆ leukemic B-cell precursors and unveiled a Klf5-dependent regulatory loop on glutamine-dependent glutathione metabolism. In summary, we describe a novel mechanism of Klf5 B-ALL suppressor activity through its direct role on the metabolism of antioxidant glutathione levels, a crucial positive regulator of leukemic precursor survival.

2018-07-10 | GSE115919 | GEO

Quantitative transcriptome analysis of a high-GSH producing Saccharomyces cerevisiae and the wild type based on the second generation sequencing.

Project description:The mutant Saccharomyces cerevisiae Y518 generated much more intracellular glutathione (GSH) than its counterpart dose. The RNA-seq based global transcriptome analysis was performed for exploring the potential mechanisms. Statistical analysis indicated that 1125 differentially expressed genes (fold-change>=2.0, FDR<=0.001) were up-regulated and 503 were down-regulated. There were 12 genes involved in glutathione metabolism. Of which GSH1, encodes gamma-glutamine cysteine synthetase, the rate-limiting enzyme in GSH biosynthesis process, was up-regulated. And MET17, encodes cysteine synthase A, an enzyme catalyzes the biosynthesis of one of the precursor amino acids L- cysteine, was also up-regulated. Besides, regulator SKN7 and several genes involved in oxidative stress response (GPX2, CTT1, SOD1, TRX2) were up-regulated. Intracellular ROS level of Y518 was also enhanced compared to that of 2-10515. Our results indicate that up-regulations of GSH1 and MET17 might be associated with the increased intracellular GSH content of the mutant, and up-regulated GSH1 may be caused by increased intracellular ROS level. Saccharomyces cerevisiae mRNA profiles of 24-h wild type 2-10515 and mutant Y518 were generated by deep sequencing using Illumina HiSeqTM 2000

2014-06-07 | E-GEOD-47787 | biostudies-arrayexpress

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

MTflEcad I80 and MTflEcad DI150 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 (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.

2022-10-15 | GSE187476 | GEO

Quantitative transcriptome analysis of a high-GSH producing Saccharomyces cerevisiae and the wild type based on the second generation sequencing.

2014-06-07 | GSE47787 | GEO

Bone Stromal Glutamine Renders Tumor cell PARP Inhibitor Resistance

Project description:The majority of patients with late-stage breast cancer develop distal bone metastases. The bone microenvironment can affect response to therapy, and uncovering the underlying mechanisms could help identify improved strategies for treating bone metastatic breast cancer. Here, we observed that osteoclasts reduced the sensitivity of breast cancer cells to DNA damaging agents, including cisplatin and the PARP inhibitor (PARPi) olaparib. Metabolic profiling identified elevated glutamine production by osteoclasts. Glutamine supplementation enhanced the survival of breast cancer cells treated with DNA damaging agents, while blocking glutamine uptake increased sensitivity and suppressed bone metastasis. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated in cancer cells following PARPi treatment through stress-induced ATF4-dependent transcriptional programming. Increased glutamine uptake and GPX4 upregulation concertedly enhanced glutathione metabolism in cancer cells to help neutralize oxidative stress and generate PARPi resistance. Analysis of paired patient samples of primary breast tumors and bone metastases revealed significant induction of GPX4 in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generated a synergistic effect in reducing bone metastasis. These results identify a role for glutamine production by bone-resident cells in supporting metastatic cancer cells to overcome oxidative stress and develop resistance to DNA-damaging therapies.

2023-11-12 | GSE208234 | GEO

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