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Simple Summary: Reactive oxygen species (ROS) are unstable derivatives of oxygen that are generated naturally as products or biproducts of biological reactions. ROS, such as hydrogen peroxide, can be utilized for defense against infectious agents and as messengers in the biological system. However, excess ROS can damage DNA, lipids, and proteins, possibly inactivating or altering their functions. The molecules utilized by the body to stop production of ROS, to neutralize excess ROS, or to repair damage caused by ROS are known as antioxidants. Peroxiredoxins (Prxs) are one of the antioxidant enzymes expressed in species from bacteria to humans that protect cells against ROS. In recent years, great progress has been made in understanding the role of Prxs in normal physiology and in different diseases. In this review, we have briefly summarized the recent findings regarding Prxs in cancer. Peroxiredoxins (Prxs) are antioxidant enzymes with ubiquitous expression in human tissues. Prxs are expressed in archaea, bacteria, and eukaryota, often in multiple isoforms. Because of their abundant expression in different cellular organelles and extraordinary sensitivity to H2O2, Prxs are among the first defenses against oxidative stress. Prxs undergo reversible oxidation to disulfides, and some family members perform chaperone or phospholipase functions upon further oxidation. Prxs are upregulated in cancer cells. Research has suggested that Prxs can function as tumor promoters in various cancers. The major objective of this review is to summarize novel findings regarding the roles of Prxs in common cancer types. Prxs have been shown to influence differentiation of inflammatory cells and fibroblasts, remodeling of extracellular matrix, and regulation of stemness. Since aggressive cancer cells have higher intracellular levels of ROS that they can utilize to proliferate and metastasize compared to normal cells, it is critical that we understand the regulation and functions of primary antioxidants such as Prxs. These small but mighty proteins could prove to be key for improving cancer therapeutics and patient survival. [ABSTRACT FROM AUTHOR]

Peroxiredoxin IV (Prx4), a typical two-cysteine-containing member of the peroxidase family, functions as an antioxidant to maintain cellular redox homeostasis through the reduction of reactive oxygen species (ROS) via cycles of oxidation–reduction reactions. Under oxidative stress, all Prxs including Prx4 are inactivated as their catalytic cysteines undergo hyperoxidation, and hyperoxidized two-cysteine Prxs can be exclusively repaired and revitalized through the reduction cycle catalyzed by sulfiredoxin (Srx). Previously, we showed that Prx4 is a preferred substrate of Srx, and knockout of Srx in mice leads to resistance to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis. To further understand the significance of the Srx/Prx4 axis in colorectal cancer development, Prx4−/− mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4−/− genotype had significantly fewer and smaller tumors. Histopathological analysis revealed that loss of Prx4 leads to increased cell death through lipid peroxidation and lower infiltration of inflammatory cells in the knockout tumors compared to wildtype. Treatment with DSS alone also showed decreased infiltration of macrophages and lymphocytes in the colon of knockout mice, suggesting a role for Prx4 in inflammatory response. In addition, loss of Prx4 caused alterations in plasma cytokines and chemokines after DSS and AOM/DSS treatments. These findings suggest that loss of Prx4 protects mice from AOM/DSS-induced colon tumorigenesis. Thus, targeting Prx4 may provide novel strategies for colon cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4−/− and Srx−/−/Prx4−/− mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients. [ABSTRACT FROM AUTHOR]

Significance: Diabetes has long been recognized as an independent risk factor for cancer, but there is insufficient mechanistic understanding of biological mediators that bridge two disorders together. Understanding the pathogenic association between diabetes and cancer has become the focus of many studies, and findings are potentially valuable for the development of effective preventive or therapeutic strategies for both disorders. Recent Advances: A summary of literature reveals a possible connection between diabetes and cancer through the family of protein disulfide isomerase (PDI). Historical as well as the most recent findings on the structure, biochemistry, and biology of the PDI family were summarized in this review. Critical Issues: PDIs in general function as redox enzymes and protein chaperones to control the quality of proteins by correcting or otherwise eliminating misfolded proteins in conditions of oxidative stress and endoplasmic reticulum stress, respectively. However, individual members of the PDI family may contribute uniquely to the pathogenesis of diabetes and cancer. Studies of exemplary members such as protein disulfide isomerase-associated (PDIA) 1, PDIA6, and PDIA15 were reviewed to highlight their contributions in the pathogenesis of diabetes and cancer and how they can be potential links bridging the two disorders through the cross talk of signaling pathways. Future Directions: Apparently ubiquitous presence of the PDIs creates difficulties and challenges for scientific community to develop targeted therapeutics for the treatment of diabetes and cancer simultaneously. Understanding molecular contribution of individual PDI in the context of specific disease may provide some insights into the development of mechanism-based target-directed therapeutics. Antioxid. Redox Signal. 37, 1191–1205. [ABSTRACT FROM AUTHOR]

Peroxiredoxin IV (Prx4) is a 2-Cysteine peroxidase with ubiquitous expression in human tissues. Prx4 scavenges hydrogen peroxide and participates in oxidative protein folding in the endoplasmic reticulum. In addition, Prx4 is secreted outside the cell. Prx4 is upregulated in several cancers and is a potential therapeutic target. We have summarized historical and recent advances in the structure, function and biological roles of Prx4, focusing on inflammatory diseases and cancer. Oxidative stress is known to activate pro-inflammatory pathways. Chronic inflammation is a risk factor for cancer development. Hence, redox enzymes such as Prx4 are important players in the crosstalk between inflammation and cancer. Understanding molecular mechanisms of regulation of Prx4 expression and associated signaling pathways in normal physiological and disease conditions should reveal new therapeutic strategies. Thus, although Prx4 is a promising therapeutic target for inflammatory diseases and cancer, further research needs to be conducted to bridge the gap to clinical application. [ABSTRACT FROM AUTHOR]

Intracellular antioxidant enzymes are critical for maintenance of redox homeostasis, but whether and how they contribute to the malignancy of cancer cells remains poorly understood. Sulfiredoxin (Srx) is a unique oxidoreductase in that it not only restores peroxidase activity of peroxiredoxins (Prxs) but also functions as a pivotal stimulator of oncogenic signaling. We found that abnormally high level of Srx promotes colorectal cancer (CRC) malignancy by stimulating gelatin degradation, invadopodia formation, and cell invasion. Fascin, an actin-bundling protein, was discovered and validated as one of the critical downstream targets of Srx activation. We demonstrated that depletion of Srx in CRC cells leads to upregulation of miR143-3p, which mediates degradation of fascin mRNA through binding to conserved sites within the 3′ untranslated region (UTR). Depletion of fascin in CRC cells recapitulates the effect of Srx loss, and restoration of fascin in Srx-depleted cells by miR143-3p inhibitor or overexpression rescues defects in cell invasion. Therefore, our data demonstrate that the Srx-miR143-fascin axis plays a key role in promoting the malignancy of human CRC cells. In the future, the Srx-miR143-fascin axis can be used as a functional pathway to evaluate the efficacy of therapeutic drugs or be targeted to develop promising chemotherapeutics for treatment of CRC patients. [ABSTRACT FROM AUTHOR]

R3848 --> Oxidative stress is an important contributing factor in many types of human disease including cancer. One of the major antioxidants involved in the maintenance of cellular redox balance is the Peroxiredoxin (Prx) family of proteins. They carry out such function through scavenging and reducing hydrogen peroxide, alkyl hydroperoxides and peroxynitrite with high sensitivity. Peroxiredoxin IV (Prx4) is one of the six members of the Prx family and is highly conserved in prokaryotes and eukaryotes. In human genome, Prx4 gene is located in the X chromosome (Xp22.11). Prx4 protein is mainly localized in the Endoplasmic Reticulum (ER) where it plays an important role in ROS scavenging as well as oxidative protein folding. It is also present in the cytoplasm and can be secreted into extracellular space under physiological conditions. Sulfiredoxin (Srx) is another enzyme that protects cells against oxidative stress by reducing hyperoxidized 2‐cysteine‐containing Prxs. Prx4 has been found to be overexpressed in a number of human cancers including colorectal cancer. Previously, we have discovered that reduced expression of Srx disrupts chemically induced colorectal cancer development in mice. However, the role of Prx4 in colon carcinogenesis has not been studied before. In this study, Prx4 null mice and Srx‐Prx4 null mice were generated in pure FVB/N background. Mouse colon carcinogenesis was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Briefly, wildtype, Prx4 null mice and Srx‐Prx4 null mice at 8‐week of age were injected intraperitoneally with 10mg/kg of AOM in week 1. Mice were administered with two rounds of 2% DSS in drinking water in weeks 2 and 10. Twenty weeks after AOM injection, all mice were euthanized and examined for tumors. Our results indicate that Prx4 null mice have significantly reduced tumor multiplicity as well as smaller tumor size. This suggests that Prx4 has a critical oncogenic role in cancer development. We are currently conducting mechanistic studies to determine how the loss of Prx4 leads to mice resistant to colon carcinogenesis in the AOM/DSS model. [ABSTRACT FROM AUTHOR]

Sulfiredoxin (Srx) reduces hyperoxidized 2-cysteine-containing peroxiredoxins (Prxs) and protects cells against oxidative stress. Previous studies have shown that Srx is highly expressed in primary specimens of lung cancer patients and plays a pivotal role in lung tumorigenesis and cancer progression. However, the oncogenic mechanisms of Srx in cancer are incompletely understood. In this study, we found that Srx knockdown sensitizes lung cancer cells to endoplasmic reticulum (ER) stress-induced cell death. Through MS analysis, we determined that Srx forms a complex with the ER-resident protein thioredoxin domain-containing protein 5 (TXNDC5). Using reciprocal co-immunoprecipitation, immunofluorescence imaging, subcellular fractionation, and domain-mapping assays with site-specific mutagenesis and purified recombinant proteins, we further characterized the Srx-TXNDC5 interaction. In response to ER stress but not to oxidative stress, Srx exhibits an increased association with TXNDC5, facilitating the retention of Srx in the ER. Of note, TXNDC5 knockdown in lung cancer cells inhibited cell proliferation and repressed anchorage-independent colony formation and migration, but increased cell invasion and activation of mitogen-activated protein kinases. Using immunohistochemical staining, we demonstrate that TXNDC5 is highly expressed in patient-derived lung cancer specimens. Bioinformatics analysis of publicly available data sets revealed that those with high Srx levels have significantly shorter survival and that those with high TXNDC5 levels have longer survival. We conclude that the cellular levels of Srx and TXNDC5 may be useful as biomarkers to predict the survival of individuals with lung cancer. [ABSTRACT FROM AUTHOR]