The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

Mishra, Murli; Jiang, Hong; Wu, Lisha; Chawsheen, Hedy A.; Wei, Qiou

doi:10.1016/j.canlet.2015.07.002

Cited by 66 publications

(64 citation statements)

References 121 publications

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“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars contribute to the regulation of cell response to ER stress and impact downstream events in protein folding. Moreover, Grx and Trx, as deglutathionylating enzymes also localize to the ER, indicating that participants in the S-glutathionylation cycle (including GSH and oxidized GSH [GSSG]) are present in this organelle (9,33). By comparing protein S-glutathionylation in cells from Gstp1/p2 wild-type and knockout mice, we were able to identify differences in a cluster of redoxactive proteins found in the ER.…”

Section: Discussionmentioning

confidence: 89%

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Zhang

Ancrum

et al. 2017

Antioxidants & Redox Signaling

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Aims: S-glutathionylation of cysteine residues, catalyzed by glutathione S-transferase Pi (GSTP), alters structure/function characteristics of certain targeted proteins. Our goal is to characterize how S-glutathionylation of proteins within the endoplasmic reticulum (ER) impact cell sensitivity to ER-stress inducing drugs. Results: We identify GSTP to be an ER-resident protein where it demonstrates both chaperone and catalytic functions. Redox based proteomic analyses identified a cluster of proteins cooperatively involved in the regulation of ER stress (immunoglobulin heavy chain-binding protein [BiP], protein disulfide isomerase [PDI], calnexin, calreticulin, endoplasmin, sarco/endoplasmic reticulum Ca 2+ -ATPase [SERCA]) that individually coimmunoprecipitated with GSTP (implying protein complex formation) and were subject to reactive oxygen species (ROS) induced S-glutathionylation. S-glutathionylation of each of these six proteins was attenuated in cells (liver, embryo fibroblasts or bone marrow dendritic) from mice lacking GSTP (Gstp1/p2 -/-) compared to wild type (Gstp1/p2 +/+ ). Moreover, Gstp1/p2 -/-cells were significantly more sensitive to the cytotoxic effects of the ER-stress inducing drugs, thapsigargin (7-fold) and tunicamycin (2-fold). Innovation: Within the family of GST isozymes, GSTP has been ascribed the broadest range of catalytic and chaperone functions. Now, for the first time, we identify it as an ER resident protein that catalyzes S-glutathionylation of critical ER proteins within this organelle. Of note, this can provide a nexus for linkage of redox based signaling and pathways that regulate the unfolded protein response (UPR). This has novel importance in determining how some drugs kill cancer cells. Conclusions: Contextually, these results provide mechanistic evidence that GSTP can exert redox regulation in the oxidative ER environment and indicate that, within the ER, GSTP influences the cellular consequences of the UPR through S-glutathionylation of a series of key interrelated proteins. Antioxid. Redox Signal. 26, 247-261.

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Section: Discussionmentioning

confidence: 89%

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Zhang

Ancrum

et al. 2017

Antioxidants & Redox Signaling

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“…Cancer cells are more dependent on antioxidant mechanisms and more vulnerable to ROS-induced damage than normal cells [38,40]. SRXN1 is an antioxidant enzyme induced by NRF2 and AP-1 and plays an important role in oxidative stress balance [67][68][69]. Specifically, SRXN1 acts in peroxiredoxin (I-IV) reactivation [70].…”

Section: Discussionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Barquilha

Santos

Monção

et al. 2020

Oxidative Medicine and Cellular Longevity

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The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

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“…Subsequently, the overexpression of Srx has already been demonstrated to promote cancer metastasis in multiple cancers [10], including those cancers we just mentioned. It is well documented that cancer cells are known to bring about numerous ROS.…”

Section: Discussionmentioning

confidence: 99%

Sulfiredoxin May Promote Cervical Cancer Metastasis via Wnt/β-Catenin Signaling Pathway

Lan

Zhao

Fan

et al. 2017

IJMS

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The abnormal elevation of sulfiredoxin (Srx/SRXN1)—an antioxidant enzyme whose main function is to protect against oxidative stress—has been shown to be closely correlated with the progression of several types of cancer, including human cervical cancer. However, the molecular mechanism by which Srx promotes tumor progression, especially cancer metastasis in cervical cancer, has not been elucidated. Here, we show that Srx expression gradually increases during the progression of human cervical cancer and its expression level is closely correlated with lymph node metastasis. Our study also reveals a significant positive correlation between the expression of Srx and β-catenin in cervical cancer tissues. Loss-of-function studies demonstrate that Srx knockdown using a lentiviral vector-mediated specific shRNA decreases the migration and invasion capacity in HeLa (human papilloma virus 18 type cervical cancer cell line) and SiHa SiHa (cervical squamous cancer cell line). Notably, the exact opposite effects were observed in gain-of-function experiments in C-33A cells. Mechanistically, downregulation or upregulation of Srx leads to an altered expression of proteins associated with the Wnt/β-catenin signaling pathway. Furthermore, blockage of the Wnt/β-catenin signaling pathway contributed to attenuated Srx expression and resulted in significant inhibition of cell migration and invasion in cervical cancer cell lines. Combined, Srx might be an oncoprotein in cervical cancer, playing critical roles in activating the Wnt/β-catenin signaling pathway; it may therefore be a therapeutic target for cervical cancer.

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The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

Cited by 66 publications

References 121 publications

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Sulfiredoxin May Promote Cervical Cancer Metastasis via Wnt/β-Catenin Signaling Pathway

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