Glutathione and Glutaredoxin Act as a Backup of Human Thioredoxin Reductase 1 to Reduce Thioredoxin 1 Preventing Cell Death by Aurothioglucose

Du, Yu‐Cang; Zhang, Huihui; Lu, Jun; Holmgren, Arne

doi:10.1074/jbc.m112.392225

Cited by 197 publications

(159 citation statements)

References 60 publications

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“…1, the physiological state of Trx1 in the untreated cells was fully reduced, in line with a previous report (24). Under oxidative stress, the redox state of Trx1 shifted from the fully reduced state to the oxidized state.…”

Section: Cellular Redox State Response Of Trx1 To Oxidative Stress-supporting

confidence: 76%

“…Because in vivo redox measurements of GSH in yeast and mammalian cells have confirmed a very reduced state for the cytosolic GSH/GSSG pool of Ϫ290 to Ϫ300 mV (29 -31), the reaction is thermodynamically possible. It was reported previously that the Grx system also works as an electron donor for reduction of the active site disulfide of human Trx1 (24). In two-disulfide Trx1, the reduction of the active site disulfide might occur after the reduction of the non-active site disulfide because the redox potential of the non-active site dithiol is higher than that of the active site.…”

Section: Discussionmentioning

confidence: 99%

“…Detection of Trx1 Redox State in Cells-The redox state of Trx1 was detected by a modified redox Western blot method described previously (22)(23)(24). To prepare mobility standards, cell lysates were denatured and unfolded with urea and fully reduced with DTT.…”

Section: Methodsmentioning

confidence: 99%

“…We treated A549 cells with a high concentration of H 2 O 2 as an oxidative stress source, and the redox state of Trx1 in cells was detected using a modified redox Western blot method. In the classic redox Western blot method (22)(23)(24), cells were lysed by 8 M urea containing IAA to alkylate the free thiols of Trx1. However, the rate for the alkylation of Trx1 with IAM was found to be 20-fold faster than that with IAA (27).…”

Section: Cellular Redox State Response Of Trx1 To Oxidative Stress-mentioning

confidence: 99%

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Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

Du¹,

Zhang²,

Zhang

et al. 2013

Journal of Biological Chemistry

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Background:The Cys-62/Cys-69 dithiol of Trx1 is predicted to have a profound effect on cell signaling. Results: The Cys-62/Cys-69 dithiol of Trx1 was oxidized by Prx1, and this disulfide was reduced by the GSH/glutaredoxin system. Conclusion: Trx1 is involved in redox regulation via reversible oxidation of the Cys-62/Cys-69 dithiol of Trx1. Significance: We demonstrated the critical role of Trx1 oxidation in cell signaling.

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Section: Cellular Redox State Response Of Trx1 To Oxidative Stress-supporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cellular Redox State Response Of Trx1 To Oxidative Stress-mentioning

confidence: 99%

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Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

Du¹,

Zhang²,

Zhang

et al. 2013

Journal of Biological Chemistry

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“…Concentrations of ebselen, ranging from 1 to 40 mM, have been widely employed in actual and past studies on different tissues and cell types, where it shows a protective action (Yamagata et al, 2008;Deng et al, 2010;Hassan et al, 2010;Yue et al, 2011;Du et al, 2012). However, as stated in the introduction, ebselen might induce cell death at certain concentrations.…”

Section: Discussionmentioning

confidence: 99%

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

Santofimia‐Castaño

Salido

González

2013

DNA and Cell Biology

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The seleno-organic compound and radical scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) have been extensively employed as an anti-inflammatory and neuroprotective compound. However, its glutathione peroxidase activity at the expense of cellular thiols groups could underlie certain deleterious actions of the compound on cell physiology. In this study, we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular viability, the intracellular free-Ca 2 + concentration ([Ca 2 + ] c ), the mitochondrial freeCa 2 + concentration ([Ca 2 + ] m ), and mitochondrial membrane potential (c m ) were analyzed. The caspase-3 activity was also assayed. Our results show that cell viability was reduced by treatment of cells with ebselen, depending on the concentration employed. In the presence of ebselen, we observed an initial transient increase in [Ca 2 + ] c that was then followed by a progressive increase to an elevated plateau. We also observed a transient increase in [Ca 2 + ] m in the presence of ebselen that returned toward a value over the prestimulation level. The compound induced depolarization of c m and altered the permeability of the mitochondrial membrane. Additionally, a disruption of the mitochondrial network was observed. Finally, we did not detect changes in caspase-3 activation in response to ebselen treatment. Collectively, these data support the likelihood of ebselen, depending on the concentration employed, reduces viability of rat hippocampal astrocytes via its action on the mitochondrial activity. These may be early effects that do not involve caspase-3 activation. We conclude that, depending on the concentration used, ebselen might exert deleterious actions on astrocyte physiology that could compromise cell function.

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Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

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Glutathione and Glutaredoxin Act as a Backup of Human Thioredoxin Reductase 1 to Reduce Thioredoxin 1 Preventing Cell Death by Aurothioglucose

Cited by 197 publications

References 60 publications

Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

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