Cytoprotective Nrf2 pathway is induced in chronically Txnrd1-deficient hepatocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE16381 | GEO | 2009/06/03
SECONDARY ACCESSION(S): PRJNA115293
REPOSITORIES: GEO
Similar Datasets
Project description:Metabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins. Here we generated mice in which the txnrd1 gene, encoding Txnrd1, was specifically disrupted in all parenchymal hepatocytes. Experiment Overall Design: Transcriptome analyses on whole mouse livers.
2009-06-24 | E-GEOD-16381 | biostudies-arrayexpress
Project description:Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletions, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1.fl/fl; Ins1.Cre/+, βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to continuous ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
2022-07-05 | GSE200965 | GEO
Project description:BackgroundMetabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins.Principal findingsHere we generated mice in which the txnrd1 gene, encoding Txnrd1, was specifically disrupted in all parenchymal hepatocytes. Txnrd1-deficient livers exhibited a transcriptome response in which 56 mRNAs were induced and 12 were repressed. Based on the global hybridization profile, this represented only 0.3% of the liver transcriptome. Since most liver mRNAs were unaffected, compensatory responses were evidently effective. Nuclear pre-mRNA levels indicated the response was transcriptional. Twenty-one of the induced genes contained known antioxidant response elements (AREs), which are binding sites for the oxidative and chemical stress-induced transcription factor Nrf2. Txnrd1-deficient livers showed increased accumulation of nuclear Nrf2 protein and chromatin immunoprecipitation on the endogenous nqo1 and aox1 promoters in fibroblasts indicated that Txnrd1 ablation triggered in vivo assembly of Nrf2 on each.ConclusionsChronic deletion of Txnrd1 results in induction of the Nrf2 pathway, which contributes to an effective compensatory response.
| S-EPMC2703566 | biostudies-literature
Project description:The thioredoxin-1 (Trx1) system is a key player of the cellular redox balance and a sensor of energy and glucose metabolism. Here we report critical c-Myc-dependent activation of the Trx1 system during glucose-driven T cell expansion during development and immune responses but endogenous Trx1-repression during quiescence. Thioredoxin-reductase-1 (Txnrd1)-deletion in CD4-CD8- thymocytes prevented their expansion, while deletion in CD4+CD8+ thymocytes did not affect further maturation and peripheral homeostasis of T-cells. Moreover, B cell development was Txnrd1-independent. Txnrd1 was critical for expansion of activated T cells. Unbiased metabolomics revealed that Txnrd1 is necessary for donating reducing equivalent to ribonucleotide reductase (RNR) at the last step of nucleotide biosynthesis. Impaired availability of 2’-deoxyribonucleotides induced the DNA damage response and cell cycle arrest of Txnrd1-deficient T cells. These results uncover a pivotal role of the Trx1 system in metabolic reprograming of thymic and peripheral T cells and provide a rationale for targeting of Txnrd1 in T-cell leukemia.
2018-03-15 | GSE107090 | GEO
Project description:Small cell lung cancer (SCLC) patients experience rapid disease progression despite frequently achieving a complete response to first-line therapy. Maintenance treatments, aiming at controlling residual tumor cells, generally fail due to cross-resistance, inability to target tumor vulnerabilities, or dose-limiting side effects. Here, we show that SCLC cells, like their cell-of-origin, pulmonary neuroendocrine cells (PNECs), exhibit notably low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a novel thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, independent of their molecular subtype and the resistance status against first-line therapy. Importantly, SCLC cells, in contrast to non-cancerous cells, cannot adapt to drug-induced ROS stress because they repress ROS defense enzymes through multiple layers of epigenetic and transcriptional mechanisms. By exploiting this differential ability to manage oxidative stress, we demonstrate that the therapeutic dose of TXNRD1 inhibitors can be safely increased in vivo through pharmacological activation of the NRF2 stress response pathway using Bardoxolon-Methyl (CDDO-Me), leading to improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors in cancers like SCLC, which are marked by reduced ROS-scavenging capacity and strong suppression of adaptive resistance mechanisms.
2024-11-11 | GSE280642 | GEO
Project description:Small cell lung cancer (SCLC) patients experience rapid disease progression despite frequently achieving a complete response to first-line therapy. Maintenance treatments, aiming at controlling residual tumor cells, generally fail due to cross-resistance, inability to target tumor vulnerabilities, or dose-limiting side effects. Here, we show that SCLC cells, like their cell-of-origin, pulmonary neuroendocrine cells (PNECs), exhibit notably low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a novel thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, independent of their molecular subtype and the resistance status against first-line therapy. Importantly, SCLC cells, in contrast to non-cancerous cells, cannot adapt to drug-induced ROS stress because they repress ROS defense enzymes through multiple layers of epigenetic and transcriptional mechanisms. By exploiting this differential ability to manage oxidative stress, we demonstrate that the therapeutic dose of TXNRD1 inhibitors can be safely increased in vivo through pharmacological activation of the NRF2 stress response pathway using Bardoxolon-Methyl (CDDO-Me), leading to improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors in cancers like SCLC, which are marked by reduced ROS-scavenging capacity and strong suppression of adaptive resistance mechanisms.
2024-11-11 | GSE279100 | GEO
Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen. Adult male wildtype and txnrd1 liver-null mice (C57BL6/J) were treated with either saline (PBS) or 100mg/kg APAP. Liver RNA was harvested eight hours after challenge and processed for microarray analysis. Comparison of 2 treatment conditions in 2 genotypes, biological replicates in triplicate.
2013-06-08 | E-GEOD-37874 | biostudies-arrayexpress
Project description:Phenotype-based screening can identify unique small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we used thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as targets. We confirmed through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identified NQO1 loss as a mechanism of LCS3 resistance. This work highlights the ability of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential therapeutic utility of inhibiting disulfide reductases in LUAD.
2022-04-04 | PXD030294 | Pride
Project description:High-throughput phenotype-based screening of large libraries of compounds can identify small molecules that elicit a desired cellular response, but additional approaches are required to find and characterize their targets and mechanisms of action. Here we show that a compound termed lung cancer screen 3 (LCS3), previously selected for its ability to impair the growth of human lung adenocarcinoma (LUAD) cell lines, but not normal lung cells, induces oxidative stress and activates the NRF2 signaling pathway by generating reactive oxygen species (ROS) in sensitive LUAD cell lines. To identify the effector that mediates this effect, we applied thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as LCS3 targets. Through enzymatic assays using purified protein, we confirmed that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are correspondingly sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR screen identified the loss of NQO1 as a mechanism of LCS3 resistance. This work highlights the power of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential utility of inhibiting disulfide reductases in treatment of LUAD.
2022-03-02 | GSE178311 | GEO
Project description:Sterile inflammation, also known as “inflammaging”, is a hallmark of tissue ageing. Cellular senescence contributes to tissue aging in part through secretion of proinflammatory factors known as senescence-associated secretory phenotype (SASP). Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living, and physical performance at old age. TXNRD1’s role in regulating tissue ageing has been attributed to its enzymatic role in reducing reactive oxygen species. Here we show that TXNRD1 drives SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independent of its enzymatic activity
2023-05-25 | GSE204841 | GEO