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Effects of redox modulation by inhibition of Thioredoxin reductase on radiosensitivity and gene expression

ABSTRACT: The involvement the thioredoxin system in radiation resistance was investigated in human lung cancer cells by a combination of ionizing radiation and specific thioredoxin reductase-inhibition by a phosphine gold compound. Gene expression profiles (Human Gene 1.0 ST) of lung cancer cells subjected to ionizing radiation and/or inhibition of thioredoxin reductase were studied. Data analyses were performed using the Affymetrix GeneChip Operating Software (GCOS) Version 1.4.

ORGANISM(S): Homo sapiens

SUBMITTER: Selenius Markus

PROVIDER: S-ECPF-GEOD-25814 | biostudies-other |

REPOSITORIES: biostudies-other

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Effects of redox modulation by inhibition of thioredoxin reductase on radiosensitivity and gene expression.

Project description:The thioredoxin system is a promising target when aiming to overcome the problem of clinical radiation resistance. Altered cellular redox status and redox sensitive thiols contributing to induction of resistance strongly connect the ubiquitous redox enzyme thioredoxin reductase (TrxR) to the cellular response to ionizing radiation. To further investigate possible strategies in combating clinical radiation resistance, human radio-resistant lung cancer cells were subjected to a combination of single fractions of γ-radiation at clinically relevant doses and non-toxic levels of a well-characterized thioredoxin reductase inhibitor, the phosphine gold(I) compound [Au(SCN)(PEt(3))]. The combination of the TrxR-inhibitor and ionizing radiation reduced the surviving fractions and impaired the ability of the U1810 cells to repopulate by approximately 50%. In addition, inhibition of thioredoxin reductase caused changes in the cell cycle distribution, suggesting a disturbance of the mitotic process. Global gene expression analysis also revealed clustered genetic expression changes connected to several major cellular pathways such as cell cycle, cellular response to stress and DNA damage. Specific TrxR-inhibition as a factor behind the achieved results was confirmed by correlation of gene expression patterns between gold and siRNA treatment. These results clearly demonstrate TrxR as an important factor conferring resistance to irradiation and the use of [Au(SCN)(PEt(3))] as a promising radiosensitizing agent.

| S-EPMC3823227 | biostudies-literature

Effects of redox modulation by inhibition of Thioredoxin reductase on radiosensitivity and gene expression

Project description:The involvement the thioredoxin system in radiation resistance was investigated in human lung cancer cells by a combination of ionizing radiation and specific thioredoxin reductase-inhibition by a phosphine gold compound. Gene expression profiles (Human Gene 1.0 ST) of lung cancer cells subjected to ionizing radiation and/or inhibition of thioredoxin reductase were studied. Data analyses were performed using the Affymetrix GeneChip Operating Software (GCOS) Version 1.4.

2010-12-03 | E-GEOD-25814 | biostudies-arrayexpress

Effects of redox modulation by inhibition of Thioredoxin reductase on radiosensitivity and gene expression

2010-12-03 | GSE25814 | GEO

Deletion of thioredoxin reductase disrupts redox homeostasis and impairs β-cell function

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

Thioredoxin and glutaredoxin-mediated redox regulation of ribonucleotide reductase.

Project description:Ribonucleotide reductase (RNR), the rate-limiting enzyme in DNA synthesis, catalyzes reduction of the different ribonucleotides to their corresponding deoxyribonucleotides. The crucial role of RNR in DNA synthesis has made it an important target for the development of antiviral and anticancer drugs. Taking account of the recent developments in this field of research, this review focuses on the role of thioredoxin and glutaredoxin systems in the redox reactions of the RNR catalysis.

| S-EPMC3942543 | biostudies-literature

Ectopic suicide inhibition of thioredoxin glutathione reductase.

Project description:Selective suicide inhibitors represent a seductively attractive approach for inactivation of therapeutically relevant enzymes since they are generally devoid of off-target toxicity in vivo. While most suicide inhibitors are converted to reactive species at enzyme active sites, theoretically bioactivation can also occur in ectopic (secondary) sites that have no known function. Here, we report an example of such an "ectopic suicide inhibition", an unprecedented bioactivation mechanism of a suicide inhibitor carried out by a non-catalytic site of thioredoxin glutathione reductase (TGR). TGR is a promising drug target to treat schistosomiasis, a devastating human parasitic disease. Utilizing hits selected from a high throughput screening campaign, time-resolved X-ray crystallography, molecular dynamics, mass spectrometry, molecular modeling, protein mutagenesis and functional studies, we find that 2-naphtholmethylamino derivatives bound to this novel ectopic site of Schistosoma mansoni (Sm)TGR are transformed to covalent modifiers and react with its mobile selenocysteine-containing C-terminal arm. In particular, one 2-naphtholmethylamino compound is able to specifically induce the pro-oxidant activity in the inhibited enzyme. Since some 2-naphtholmethylamino analogues show worm killing activity and the ectopic site is not conserved in human orthologues, a general approach to development of novel and selective anti-parasitic therapeutics against schistosoma is proposed.

| S-EPMC7583042 | biostudies-literature

Subcellular Localization of Thioredoxin/Thioredoxin Reductase System—A Missing Link in Endoplasmic Reticulum Redox Balance

Project description: Not available

| S-EPMC11204020 | biostudies-literature

Thioredoxin reductase from Thermoplasma acidophilum: a new twist on redox regulation.

Project description:Thioredoxin reductases (TrxRs) regulate the intracellular redox environment by using NADPH to provide reducing equivalents for thioredoxins (Trxs). Here we present the cloning and biochemical characterization of a putative TrxR (Ta0984) and a putative Trx (Ta0866) from Thermoplasma acidophilum. Our data identify Ta0866 as a Trx through its capacity to reduce insulin and be reduced by Escherichia coli TrxR in a NADPH-dependent manner. Our data also establish Ta0984 as a TrxR due to its ability to reduce T. acidophilum Trx ( taTrx), although not in a NADPH- or NADH-dependent manner. To explore the apparent inability of taTrxR to use NADPH or NADH as a reductant, we carried out a complete electrochemical characterization, which suggests that redox potential is not the source of this nonreactivity [Hamill et al. (2008) Biochemistry 47, 9738-9746]. Turning to crystallographic analysis, a 2.35 A resolution structure of taTrxR, also presented here, shows that despite the overall structural similarity to the well-characterized TrxR from E. coli (RMSD 1.30 A (2) for chain A), the "NADPH binding pocket" is not conserved. E. coli TrxR residues implicated in NADPH binding, H175, R176, R177, and R181, have been substituted with E185, Y186, M187, and M191 in the ta protein. Thus, we have identified a Trx and TrxR protein system from T. acidophilum for which the TrxR shares overall structural and redox properties with other TrxRs but lacks the appropriate binding motif to use the standard NADPH reductant. Our discovery of a TrxR that does not use NADPH provides a new twist in redox regulation.

| S-EPMC2804746 | biostudies-literature

The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity

Project description:Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

2024-04-04 | GSE263176 | GEO

Antitumor indolequinones induced apoptosis in human pancreatic cancer cells via inhibition of thioredoxin reductase and activation of redox signaling.

Project description:Indolequinones (IQs) were developed as potential antitumor agents against human pancreatic cancer. IQs exhibited potent antitumor activity against the human pancreatic cancer cell line MIA PaCa-2 with growth inhibitory IC(50) values in the low nanomolar range. IQs were found to induce time- and concentration-dependent apoptosis and to be potent inhibitors of thioredoxin reductase 1 (TR1) in MIA PaCa-2 cells at concentrations equivalent to those inducing growth-inhibitory effects. The mechanism of inhibition of TR1 by the IQs was studied in detail in cell-free systems using purified enzyme. The C-terminal selenocysteine of TR1 was characterized as the primary adduction site of the IQ-derived reactive iminium using liquid chromatography-tandem mass spectrometry analysis. Inhibition of TR1 by IQs in MIA PaCa-2 cells resulted in a shift of thioredoxin-1 redox state to the oxidized form and activation of the p38/c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway. Oxidized thioredoxin is known to activate apoptosis signal-regulating kinase 1, an upstream activator of p38/JNK in the MAPK signaling cascade and this was confirmed in our study providing a potential mechanism for IQ-induced apoptosis. These data describe the redox and signaling events involved in the mechanism of growth inhibition induced by novel inhibitors of TR1 in human pancreatic cancer cells.

| S-EPMC3286294 | biostudies-literature

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