Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells

Cohen-Kutner, Moshe; Khomsky, Lena; Trus, Michael; Aisner, Yonatan; Niv, Masha Y.; Benhar, Moran; Atlas, Daphné

doi:10.1016/j.bcp.2013.01.003

Cited by 36 publications

(46 citation statements)

References 53 publications

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“…TrxR maintains reduced Trx and is important in controlling apoptosis (24). Cox et al showed that ARF-induced apoptosis in Jurkat T-lymphoma cells was associated with oxidation of mitochondrial Prx 3 (25) and a recent study also showed ARF caused Trx oxidation (25), showing that ARF-induced inhibition of TrxR disrupts the Trx/TrxR redox system. Similarly, BSO, a well-known inhibitor of ␥-glutamylcysteine synthetase (␥-GCS) is a widely used tool to lower GSH (26) and disrupt the GSH redox system.…”

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confidence: 99%

Selective Targeting of the Cysteine Proteome by Thioredoxin and Glutathione Redox Systems

Roede

Walker

et al. 2013

Molecular & Cellular Proteomics

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Thioredoxin (Trx) and GSH are the major thiol antioxidants protecting cells from oxidative stress-induced cytotoxicity. Redox states of Trx and GSH have been used as indicators of oxidative stress. Accumulating studies suggest that Trx and GSH redox systems regulate cell signaling and metabolic pathways differently and independently during diverse stressful conditions. In the current study, we used a mass spectrometry-based redox proteomics approach to test responses of the cysteine (Cys) proteome to selective disruption of the Trx-and GSH-dependent systems. Auranofin (ARF) was used to inhibit Trx reductase without detectable oxidation of the GSH/GSSG couple, and buthionine sulfoximine (BSO) was used to deplete GSH without detectable oxidation of Trx1. Results for 606 Cys-containing peptides (peptidyl Cys) showed that 36% were oxidized more than 1.3-fold by ARF, whereas BSO-induced oxidation of peptidyl Cys was only 10%. Mean fold oxidation of these peptides was also higher by ARF than BSO treatment. Analysis of potential functional pathways showed that ARF oxidized peptides associated with glycolysis, cytoskeleton remodeling, translation and cell adhesion. Of 60 peptidyl Cys oxidized due to depletion of GSH, 41 were also oxidized by ARF and included proteins of translation and cell adhesion but not glycolysis or cytoskeletal remodeling. Studies to test functional correlates showed that pyruvate kinase activity and lactate levels were decreased with ARF but not BSO, confirming the effects on glycolysis-associated proteins are sensitive to oxidation by ARF. These data show that the Trx system regulates a broader range of proteins than the GSH system, support distinct function of Oxidative stress is associated with numerous human diseases and results from alteration in cellular redox systems (1-3). Cellular redox mechanisms and signaling are controlled by two major thiol antioxidants, thioredoxin (Trx) 1 and glutathione (GSH). The Trx system, composed of Trx, Trx reductase (TrxR), Trx peroxidase/peroxiredoxin (Prx), and NADPH, has a wide range of cellular activities in redox control, cell proliferation, growth and survival, regulation of transcription, and cell morphology and structure (4 -6). The Trx family includes evolutionary conserved proteins that contain two catalytically active cysteine (Cys) residues that can reduce disulfide bonds of numerous target proteins in the Cys proteome, e.g. apoptosis signaling kinase-1 (ASK-1), Trx1-interacting protein (Txnip), transcription factors, and actin. In addition to catalytic activity, Trx binds to target proteins and further controls protein activity and biological function. For example, ASK-1 binds to Trx in physiologic conditions; however, under stressful conditions, it is dissociated from Trx, which then stimulates apoptotic signaling leading to cell death (7). The diverse functions of Trx suggest a nonspecific nature to its function, yet kinetic studies also show differences in activities with different substrates (8 -10), implying that an underlying redox organi...

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confidence: 99%

Selective Targeting of the Cysteine Proteome by Thioredoxin and Glutathione Redox Systems

Roede

Walker

et al. 2013

Molecular & Cellular Proteomics

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“…Froscio et al have demonstrated that AF enhanced the phosphorylation of EGFR in the epidermoid carcinoma cell lines [15]. Some studies also showed that AF caused phosphorylation of P38MAPK, ERK, JNK, and MAPKAPK2 [16,17], however, whether similar processes occur in RPE cells is not clear. Our present results confirm and expand upon these earlier findings in the context of cultured human RPE cells.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have showed that AF inhibited EGF binding to HeLa cells and enhanced protein kinase C-mediated EGFR phosphorylation in epidermoid carcinoma cell line [14,15]. It was also reported that AF can activate different kinases participating in signaling cascades controlling cellular responses to cytokines and stress, like P38MAPK, ERK, and JNK [16,17]. In our previous study, we found that AF inhibited cell survival in endothelial cell lines that were derived from axillary lymph node/vascular epithelium by down-regulating vascular endothelial growth factor receptor-3 and inducing P38MAPK phosphorylation [18].…”

Section: Introductionmentioning

confidence: 99%

Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway

Chen

Tzekov

et al. 2016

PLoS ONE

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Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner. Application of AF induced several effects: a significant decrease in total epidermal growth factor receptor (EGFR) and an increase in phosphorylated EGFR and mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase (ERK), P38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), c-Jun, mitogen activated protein kinase activated protein kinase 2(MAPKAPK2), and heat shock protein 27 (HSP27). AF also inhibited epidermal growth factor (EGF)-dependent cell proliferation and migration through affecting EGFR/MAPK signaling. The antioxidant N-acetylcysteine (NAC) blocked the AF-induced increase of reactive oxygen species (ROS) production, the reduction of total EGFR, and the phosphorylation of multiple nodes in EGFR/MAPK signaling pathway. P38MAPK inhibitor SB203580, but not inhibitors of EGFR (erlotinib), ERK (FR180204) and JNK (SP600125), suppressed AF-induced phosphorylation of EGFR/p38MAPK/MAPKAPK2/Hsp27. In conclusion, the ROS-dependent phosphorylation of EGFR/MAPK is an important signaling pathway for AF-induced inhibition of RPE cell survival, and AF may have the potential for treatment of abnormal survival of RPE cells in PVR.

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“…The stimulation of cell membrane scrambling is at least in part the result of oxidative stress, a well known trigger of suicidal erythrocyte death [34]. In nucleated cells auranofin has been shown to lower thioredoxin (Trx)-2 reductase activity, to decrease antioxidant GSH and to induce oxidative stress [18][19][20][21][22][23][24][25]. In erythrocytes the effect of auranofin was virtually abolished by the antioxidant N-acetyl-cysteine, an observation highlighting the significance of oxidative stress in the triggering of eryptosis by auranofin.…”

Section: Discussionmentioning

confidence: 99%

“…The proapoptotic effect of auranofin has been attributed to increase of cytosolic Ca 2+ activity [17], thioredoxin (Trx)-2 reductase inhibition, GSH decline and oxidative stress [18][19][20][21][22][23][24][25], p38 protein kinase activation [26], FOXO3 activation [27], as well as annexin V expression and translocation [28]. Moreover, auranofin has been shown to inhibit PGE 2 formation [5].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Eryptosis Following Auranofin Exposure

Alzoubi

Egler

Abed

et al. 2015

Cell Physiol Biochem

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Background/Aims: The antiinflammatory, antimicrobial and anticancer drug auranofin has previously been shown to trigger apoptosis, the suicidal death of nucleated cells. Side effects of the drug include anaemia. At least in theory the anaemia could result from stimulation of suicidal death of erythrocytes or eryptosis, which involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Methods: Stimulators of eryptosis include oxidative stress and increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). In the present study, phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, reactive oxygen species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and [Ca²⁺]_i from Fluo3-fluorescence. Results: A 24 hours exposure of human erythrocytes to auranofin (≥5 µg/ml) significantly increased the percentage of annexin-V-binding cells (from 2.2 ± 0.5 to 17.4 ± 1.5%), significantly decreased forward scatter and significantly enhanced ROS. At higher concentrations (10 µg/ml) auranofin triggered slight hemolysis (from 2.1 ± 0.2 to 3.2 ± 0.3%). Conclusions: Auranofin stimulates cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress.

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Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells

Cited by 36 publications

References 53 publications

Selective Targeting of the Cysteine Proteome by Thioredoxin and Glutathione Redox Systems

Selective Targeting of the Cysteine Proteome by Thioredoxin and Glutathione Redox Systems

Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway

Enhanced Eryptosis Following Auranofin Exposure

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