Redox homeostasis is critical for normal cellular function, and cellular redox imbalance is associated with a number of human pathologies including cardiovascular disease and cancer (Ye et al. 2015). Reactive oxygen species (ROS) include the superoxide anion (O2●─), hydrogen peroxide (H2O2), and hydroxyl radicals (●OH). Both exogenous and endogenous sources contribute to intracellular ROS levels. Environmental sources of ROS include ionizing radiation and certain drugs and toxins. The major endogenous source of ROS to be recognized is electrons leaking prematurely from mitochondrial electron transport chain complexes I and III that reduce molecular oxygen to superoxide anion. The superoxide produced is rapidly converted to hydrogen peroxide by spontaneous dismutation or by the activity of superoxide dismutase enzymes, and the hydrogen peroxide thus produced acts as a second messenger in cellular signaling pathways. Although low levels of hydrogen peroxide promote cell proliferation, differentiation, and migration, high levels damage cellular components such as DNA, proteins, and unsaturated lipids and result in cell death. Consequently, controlling the cellular level of ROS is of critical importance.
Oxidative stress ensues when the level of ROS exceeds the antioxidant capacity of the cell, and cells possess a host of antioxidant enzymes and small molecule antioxidants that function to maintain redox homeostasis (Ye et al. 2015). The enzymatic antioxidant defense system is composed of several enzyme families including superoxide dismutase, which catalyzes the dismutation of superoxide to hydrogen peroxide, and glutathione peroxidase, catalase, and peroxiredoxins (Prx), which reduce hydrogen peroxide to water. The sulfur of cysteine (Cys) residues can exist in a number of chemical forms including thiol (S─H), thiolate anion (S−), disulfide (S─S), sulfenic acid (S─OH), sulfinic acid (S─O2H), and sulfonic acid (S─O3H). This versatility of sulfur chemistry is of paramount importance for maintaining redox homeostasis and redox signaling. The tripeptide glutathione (GSH) comprising glutamate-glycine-cysteine is present at millimolar concentrations in cells, and GSH is the primary cellular small molecule antioxidant (Townsend et al. 2003). GSH is in equilibrium with GSH disulfide (GSSG) in cells, and the ratio of reduced (GSH) to oxidized (GSSG) glutathione is indicative of the level of oxidative stress. The intracellular environment is reducing, and the GSH to GSSG ratio is typically 100:1, but during oxidative stress, this ratio can be reduced to 10:1 or even less. In addition to acting as the primary small molecule antioxidant, the formation of mixed disulfides between proteins and GSH (P─S─SG) – i.e., protein glutathionylation – is a mechanism to prevent the oxidation of Cys residues to sulfinic and sulfonic states that may inactivate proteins or target them for degradation. The posttranslational glutathionylation modification of proteins is also involved in cell signaling (Townsend et al. 2003). The pKa of a typical Cys residue is ∼8.5, so most Cys residues exist as sulfhydryls in the reducing environment of the cytosol. However, some Cys residues have much lower pKa values, due to the presence of neighboring positively charged residues such as lysine and arginine that stabilize the thiolate anion. The thiolate anion is much more readily oxidized by ROS than sulfhydryls. Thus, when cells are exposed to oxidative stress, low pKa Cys residues in proteins are readily oxidized to cysteine sulfenic acids. These cysteine sulfenic acids can condense with the free sulfhydryls of other Cys residues to form disulfides including mixed disulfides with glutathione or can further be oxidized to sulfinic or sulfonic acids. Thus, through their ability to modify Cys residues, ROS acts as signaling molecules by altering protein structure and function. For example, one mechanism whereby hydrogen peroxide can act as a second messenger involves the oxidative inactivation of phosphatases, the catalytic cysteine of which exists as a thiolate anion. Redox regulation of protein Cys residues is known to regulate the structure and function of a number of proteins including peroxiredoxins, actin, and some protein tyrosine phosphatases (Circu and Aw 2010).
Peroxiredoxins and the Identification of Sulfiredoxin
During a transient intracellular burst of peroxides or oxidative stress, the C P -SOH intermediate can react with another H2O2 molecule to yield the inactive cysteine sulfinic acid (C P -SO2H) (Fig. 1) . Interestingly, eukaryotic typical 2-Cys Prxs are much more susceptible to the hyperoxidative inactivation than their prokaryotic homologs, and the susceptibility appears from two conserved sequence and structural motifs near the active site (Wood et al. 2003a). The loop containing the GGLG motif and the helix containing the YF motifs are present only in peroxide-sensitive, typical 2-Cys Prxs (Prx1–4), and they pack next to each other and bury the active site helix containing C P . These features slow the ability of the C R -SH from the adjacent subunit of the dimer (>13 Å) to form an S-S bond with the C P -SOH intermediate and render the C P -SOH intermediate of eukaryotic Prxs susceptible to hyperoxidation to C P -SO2H. Such oxidation of Cys residue to the sulfinic acid form was initially considered to be irreversible, but careful analyses of the fate of human hyperoxidized Prx1 revealed that the sulfinic acid modification of Prx1 is actually reversible (Woo et al. 2003), begging the question of which enzyme is responsible for this sulfinic acid reductase activity.
Sulfiredoxin (Srx) was subsequently identified as a sulfinic acid reductase in S. cerevisiae that catalyzes the ATP/Mg2+-dependent reduction of C P -SO2H back to C P -SOH in the yeast 2-cys Prx, Tas1. Srx was markedly induced by H2O2 exposure and deletion of Srx reduced tolerance to H2O2 (Biteau et al. 2003). Soon thereafter, the mammalian orthologues of yeast Srx were characterized in mice, rats, and humans (Chang et al. 2004) and demonstrated in vitro to have sulfinic acid reductase activity specific to the typical 2-Cys Prxs (Prx1–4) (Woo et al. 2005). In response to oxidative stress, the cytosolic form of mammalian Srx can be translocated into mitochondria to reduce not only the cytosolic forms of sulfinic 2-Cys Prxs (Prx1 and 2) but also the mitochondrial sulfinic 2-Cys Prx3. In mitochondria, Srx significantly decreases the collapsing rates of mitochondrial membrane potential and gives an enhanced cellular resistance against apoptosis (Noh et al. 2009). However, it remains uncertain whether Srx can be translocated into ER to reduce the ER form of sulfinic 2-Cys Prx4. The reduction of hyperoxidized Prxs by Srx was found to be a slow process that required ATP hydrolysis, and both GSH and Trx were identified as potential electron donors as their Km values were in the physiological range and similar Vmax values were obtained with both reductants (Chang et al. 2004). The fact that Srx is conserved only among eukaryotes, with some exceptions in cyanobacteria, is consistent with the observation that eukaryotic Prxs are much more susceptible to hyperoxidative inactivation. The slow rate of Prx reactivation via Srx-dependent reduction may have been co-evolutionarily selected to accommodate the intracellular messenger function of H2O2. Rapid reactivation of the inactivated Prx enzymes would reduce the amount of time available for H2O2 to accumulate and propagate its signal. Hyperoxidation also increases the ATP-independent chaperone activity of Prx, which stabilizes Prx into decameric (ring-shaped assemblies of five dimers) and higher-order oligomeric (stacked or intercalated decamers) forms that are capable of preventing aggregation of heat-denatured model substrates (Jang et al. 2004; Moon et al. 2005; Hall et al. 2011; Saccoccia et al. 2012).
Mechanism of Sulfiredoxin as a Sulfinic Acid Reductase
The mechanism of cysteine sulfinic acid reduction by Srx was originally proposed to involve ATP-dependent activation of Prx sulfinic acid by phosphorylation, followed by a thiol-mediated reduction step involving the conserved cysteine (Cys84 for yeast Srx), through two novel intermediates, a sulfinic phosphoryl ester (Prx-C P -SO2PO32−) and a thiosulfinate (Prx-C P -SO-S-Cys-Srx) (Biteau et al. 2003). An alternate reaction scheme has been proposed whereby the initial step is attack of the conserved cysteine (Cys99 for human Srx and Cys98 for rat Srx) on the γ-phosphate of ATP generating a Srx thiophosphate intermediate that is then attacked by the Prx sulfinic acid generating the same Prx-C P -SO2PO32− intermediate, followed by a thiol-mediated reduction step involving GSH instead of Srx generating Prx-C P -SO-S-G (Jeong et al. 2006). Although some experimental evidence has been interpreted to support the alternate scheme (reviewed in (Jonsson and Lowther 2007)), the preponderance of evidence, especially studies both on the human enzyme from Lowther’s group (Jonsson et al. 2005, 2008a, b, c, 2009) and on the S. cerevisiae enzyme from Rahuel-Clermont’s group (Roussel et al. 2008, 2009, 2011), suggests that the original scheme whereby Srx acts as both a phosphotransferase and a thioltransferase is correct (Fig. 1) .
Analyses of the biochemical and crystal structure of human Srx (Jonsson et al. 2005), human Srx in complex with ATP and Mg2+ (Jonsson et al. 2008b), human Srx–Prx1 complex (Jonsson et al. 2008a), and human Srx in complex with human Prx1, ATP, and Mg2+ (Jonsson et al. 2009) support the concept that phosphorylation of Prx-C P -SO2− is the first reaction step. The ATP molecule, bound tightly to the human Srx N-terminal GCHR motif through hydrogen bonding, is brought in close proximity to the sulfinic acid moiety of the Prx. The direct attack of the Prx-C P -SO2− on the γ-phosphate of ATP generates the Prx-C P -SO2PO32− intermediate. Furthermore, using chemical quenching and mass spectrometry, the exclusive formation of a thiosulfinate intermediate between hPrx2 and hSrx (Prx-C P -SO-S-Cys99-Srx) was observed (Jonsson et al. 2008c). Similarly, in S. cerevisiae, Prx-C P -SO2− is first activated by a slow, rate-limiting formation of an anhydride bond with the γ-phosphate of ATP, leading to a Prx-C P -SO2PO32− intermediate (Roussel et al. 2011), which is then reduced by an attack of the Srx catalytic Cys, resulting in a Prx-C P -SO-S-Cys84-Srx intermediate (Roussel et al. 2008).
For the S. cerevisiae Srx, the catalytic cycle is completed by (i) the attack of the Prx-C P -SO-S-Cys84-Srx by a second Srx Cys residue at position 48, leading to formation of an oxidized form of Srx with an intramolecular disulfide (Cys48-S-S-Cys84) intermediate, and (ii) the reduction of this intermediate selectively by Trx/NTR and NADPH system. This mechanism has been described both in vitro (Roussel et al. 2009) and in vivo (Boukhenouna et al. 2015). However, lack of Cys48 in mammals and plants indicates that the 1-Cys Srx utilizes a mechanism different from the one proposed for the yeast enzyme. Indeed, recent studies provided both in vitro and in vivo evidence of the role of GSH as the primary reducer of 1-Cys Srx. GSH binds to the Prx-C P -SO-S-Cys-Srx intermediate, by following saturation kinetics with an apparent dissociation constant of 34 μM, generating S-glutathionylated Srx as a catalytic intermediate which is efficiently reduced by the glutaredoxin/glutathione reductase (Grx/GR) system (Boukhenouna et al. 2015). Since this study used S. cerevisiae Srx mutants lacking Cys48 as a model, it would be interesting to further validate the results using mammal Srx which contains only one cysteine as a model.
Sulfiredoxin as a Deglutathionylating Enzyme
Another important action of Srx involves reversing glutathionylation of several proteins in eukaryotes (Findlay et al. 2006; Park et al. 2009). This observation has important implications for cell signaling because, as noted above, glutathionylation of protein cysteine residues is a posttranslational modification that affects protein structure and function. In vitro studies showed that human Prx1 can be glutathionylated at three of the four cysteine residues, including C P (Cys52), C R (Cys173), and Cys83, and the deglutathionylation of Cys83 and Cys173 is preferentially catalyzed by Srx, whereas deglutathionylation of Cys52 is preferentially catalyzed by glutaredoxin (Park et al. 2009). Notably, the Cys83 in human Prx1 is located at the dimer-dimer interface and can form a disulfide bond with the Cys83 of another subunit and shift the dimer-decamer equilibrium in favor of decamer formation (Lee et al. 2007). Blockage of the Cys83-Cys83 disulfide formation by Cys83 glutathionylation was found to be sufficient to reverse the equilibrium to favor the dimer, with a simultaneous loss of molecular chaperone activity (Park et al. 2011). Thus, deglutathionylation of Cys83 by Srx is expected to change the quaternary structure of Prx1. Prx1 has been found to interact with ∼20 proteins and to affect the functions of such target proteins (Rhee and Woo 2011). Interaction with signaling proteins such as MST1 kinase was shown to be dependent on the quaternary structure of Prx1 (Morinaka et al. 2011). Altogether, these results suggest a possible link between Srx, Prx1 glutathionylation, and the activity of the signaling pathways mediated by the Prx1-interacting proteins.
Unlike the sulfinic acid reducing function of Srx that is exclusive to 2-Cys Prxs, the deglutathionylation carried out by Srx seems to have broader substrate specificity. Human embryonic kidney (HEK293) cells transfected with Srx exhibit a decrease in global protein glutathionylation following PABA/NO (a potent inducer of glutathionylation of a number of proteins (Townsend et al. 2006)) treatment compared with control cells. Actin and protein tyrosine phosphate 1B (PTP1B) were identified in vitro as specific targets of Srx deglutathionylation activity, and these interactions were confirmed with in vivo studies. Importantly, it was shown that glutathionylation of PTP1B inhibits its enzymatic activity and that deglutathionylation of PTP1B by Srx restored the phosphatase activity of PTP1B (Findlay et al. 2006), thus indicating an interesting cross talk between glutathionylation/deglutathionylation and phosphorylation/dephosphorylation.
Sulfiredoxin as a Denitrosylating Enzyme
Protein S-nitrosylation, the covalent attachment of a –NO group to a cysteine thiol, constitutes another redox posttranslational modification that regulates the function of numerous proteins (Hess and Stamler 2012; Nakamura and Lipton 2016). Recent studies demonstrate that human Prx2 is nitrosylated and that Srx is capable of reversing this modification in an ATP-dependent manner (Sunico et al. 2016). Among the antioxidant Prx enzymes, Prx2 is the most abundant in mammalian neurons, making it a prime candidate to defend against oxidative stress. The peroxidase activities of human Prx2 have been shown to be inhibited by S-nitrosylation (Prx2-Cys-SNO) of its critical cysteine residues, including C P (Cys52) and C R (Cys173), thus promoting the oxidative stress-mediated neuronal cell death in Parkinson’s disease (PD) (Fang et al. 2007). Accordingly, overexpression of Srx, by decreasing S-nitrosylated Prx2, protects dopaminergic neural cells and human-induced pluripotent stem cell-derived neurons against NO-induced oxidative stress (Sunico et al. 2016). Therefore, Srx may be a valuable therapeutic target for neurodegenerative diseases such as PD that involve nitrosative/oxidative stress.
In sum, Srx impacts redox signaling pathways by both regulating hydrogen peroxide levels through reactivation of hyperoxidized Prxs and by reversing protein S-glutathionylation and S-nitrosylation.
Sulfiredoxin as a Redox-Independent Nuclease Enzyme
In addition to its role in sulfinic acid reduction, deglutathionylation, and denitrosylation, Srx was shown to possess nuclease activity (Chi et al. 2012). Based on the significant sequence and structural similarity of eukaryotic Srx with ParB (Basu and Koonin 2005), a nuclease enzyme in bacteria, the nucleic acid binding and hydrolyzing activity of the recombinant Srx in Arabidopsis (AtSrx), was examined, and the results indicated that AtSrx functions as a nuclease enzyme that can use single-stranded and double-stranded DNAs as substrates. By point-mutating Cys to Ser, it was demonstrated that the active site cysteine (Cys72 for plant Srx) that is critical for a sulfinate reductase function does not involve its nuclease function (Chi et al. 2012).
Regulation of Sulfiredoxin Expression
Several studies demonstrate that mammalian Srx is a target gene of the activator protein-1 (AP-1) (Glauser et al. 2007; Papadia et al. 2008; Wei et al. 2008). AP-1 binds DNA as a dimer composed of proteins of Fos and Jun families, forming either Jun/Jun homodimer or Fos/Jun heterodimer. The first indication that the Srx gene might be regulated by AP-1 came from a genome-scaled approach to identify glucose and cAMP-induced immediate-early genes and their targets in rodent pancreatic beta cells (Glauser et al. 2007). AP-1 and Srx were sequentially induced after stimulation, and three predictive AP-1 binding sites in Srx promoter, with sequences 5′-TGAGTCA-3′ or 5′-TGCGTCA-3′, were found to be both sufficient and necessary for Srx transcription (Glauser et al. 2007; Jeong et al. 2012). The proximal AP-1 binding sequence of the Srx promoter is fully conserved across mammals, whereas the distal and central sequences are partially conserved (Jeong et al. 2012). AP-1 induction of Srx expression was also observed in studies of rat neurons that are highly sensitive to oxidative damage (Papadia et al. 2008). In this study, synaptic activity acting through NMDA receptor signaling activated transcription of genes involved in intrinsic antioxidant defenses, including Srx. Mutation of either the proximal or the distal AP-1 binding site alone attenuated transcriptional induction of Srx by synaptic activity, and mutation of both sites abolished induction completely (Papadia et al. 2008). Another group utilized the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate) that activates AP-1 through ASK1/JNK cascade and TAM67, a dominant negative form of c-Jun, to show that Srx is an AP-1 target gene in mouse epidermal cells (Wei et al. 2008). Srx expression was upregulated by TPA treatment and downregulated by co-expression of TAM67. Mutation of either AP-1 binding site attenuated the Srx promoter activities. Srx was shown to be critical for oncogenic transformation, and several human skin malignancies demonstrated elevated Srx protein levels (Wei et al. 2008).
Srx expression is also regulated by nuclear factor erythroid 2-related factor (Nrf2). Nrf2 is a transcription factor that binds as heterodimers with members of the Maf protein family to antioxidant response elements (ARE) in promoters of target genes whose products are involved in protecting cells from oxidative stress. In the basal state, Nrf2 is targeted for degradation by Kelch-like ECH-associated protein (Keap1). Oxidative stress and chemopreventive agents such as D3T (3H-1,2-dithiole-3-thione) inhibit Keap1 and lead to the accumulation of Nrf2 resulting in increased expression of ARE-containing Nrf2 target genes. As mentioned, Prxs, especially Prx2, are important in protecting neuronal cells from oxidative stress. In rat neurons, the chemopreventive inducer D3T that activates Nrf2 was shown to induce Srx expression, prevent Prx hyperoxidation, and protect neurons against oxidative neuronal apoptosis (Soriano et al. 2008). Induction of Srx expression was demonstrated to be directly regulated by Nrf2, acting via a cis-acting ARE (5′-TCACCCTGAGTCAGGG-3′) in the Srx promoter (Soriano et al. 2008). The ARE in Srx contains an embedded AP-1 site (5′-TGAGTCA-3′) which directs induction of Srx by synaptic activity (Papadia et al. 2008; Jeong et al. 2012). Nrf2 induction of Srx expression was also observed in human lung cell lines (BEAS2B and A549) with constitutively activated Nrf2 due to Keap1 mutation and in the lungs of mice exposed to cigarette smoke (Singh et al. 2009). The functional ARE in the Srx promoter identified in this study is in a different orientation and slightly different position relative to the first identified ARE (Jeong et al. 2012; Singh et al. 2009). Furthermore, stimulation of mouse macrophages with lipopolysaccharide significantly induces Srx expression in both AP-1 and Nrf2-dependent manners (Kim et al. 2010) .
Sulfiredoxin in Tumorigenesis and Cancer Progression
The main function of Srx is to protect host cells from oxidative damage. Indeed, several studies have shown that Srx is induced by a variety of stimuli causing oxidative stress and plays a protective role. Srx protects against cigarette smoke-induced oxidative stress in the lung (Singh et al. 2009; Sarill et al. 2015; Rogers et al. 2017) and against pyrazole or alcohol-induced oxidative injury in the liver (Bae et al. 2011, 2012) and exhibits neuroprotective effects from oxidative/nitrosative damage (Sunico et al. 2016; Yu et al. 2015; Zhou et al. 2015a, b). However, this property of the Srx system becomes harmful to host organism when it starts protecting the survival of tumor cells (Mishra et al. 2015). Growing evidence has shown that Srx is highly expressed in several tumors compared with corresponding normal tissues, and it was found to be required for colony formation, migration, and invasion of cancer cells. Srx expression is positively correlated with cancer progression, poor prognosis, and poor survival.
Srx is highly expressed in human lung cancer, especially in tumor tissues of advanced or metastatic squamous cell carcinoma, possibly due to its antioxidant capacity to compensate for the high rate of mitochondrial metabolism in lung cancer (Kim et al. 2011; Wei et al. 2011). Knockdown of Srx reduces colony formation, migration, and invasion of human lung cancer cells. Disruption or enhancement of the Srx-Prx4 axis leads, respectively, to reduction or acceleration of tumor growth and metastasis formation in vivo. Srx-Prx4 axis is critical for lung cancer maintenance and metastasis, suggesting that targeting the Srx-Prx4 axis may provide unique effective strategies for cancer prevention and treatment (Wei et al. 2011). Immunohistochemical analysis of a large set of lung carcinomas showed that smokers and ex-smokers had significantly more Srx expression in their lung tumors, and in patients receiving cytostatic drugs or radiation therapy, Srx expression predicted a poor prognosis (Merikallio et al. 2012).
Srx is also preferentially expressed in human colorectal cancer cells, and the levels of expression are associated with patients’ clinical stages. Loss-of-function studies demonstrated that knockdown of Srx in poorly differentiated colorectal cancer cells not only leads to the inhibition of colony formation and cell invasion in vitro but also reduces tumor xenograft growth and represses metastasis to distal organs in a mouse orthotopic implantation model. Notably, exactly opposite effects were observed in gain-of-function experiments when Srx was ectopically expressed in well-differentiated colorectal cancer cells (Jiang et al. 2015). In addition, loss of Srx renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis (Wei et al. 2013). Furthermore, atmospheric pressure gas plasma-resistant colorectal cancer cells had higher basal levels of Nrf2 and Srx, and silencing both Nrf2 and Srx sensitized cancer cells to ROS-mediated cell death, indicating Nrf2/Srx axis as a central target in drug-resistant colorectal cancer treatment (Ishaq et al. 2014). In addition to its oncogenic role in lung and colorectal cancer, aberrant Srx expression has been associated with poor survival in pancreatic adenocarcinoma (Soini et al. 2014), and loss of Srx has been shown to protect mice from DMBA/TPA (7,12-dimethylbenz[α]anthracene/12-O-tetradecanoylphorbol-13-acetate)-induced skin tumorigenesis (Wu et al. 2014).
Because of metabolic and signaling aberrations, many types of cancer cells exhibit elevated ROS levels and increased antioxidant capacity as an adaption to intrinsic oxidative stress. Disruption of redox homeostasis caused by a decline in antioxidant capacity has been a strategy for effective cancer treatment (Gorrini et al. 2013). The fact that Srx is highly expressed in several tumors and is positively correlated with cancer progression indicates that targeting Srx may have some therapeutic values. Two Srx inhibitors have recently been developed, and both have been shown in vitro and in vivo to kill the human lung and ovarian cancer cells selectively and effectively by increased accumulation of sulfinic Prxs and ROS-mediated mitochondrial damage and apoptosis (Kim et al. 2016a, b).
Although the importance of Srx in various tumor types is well established, the mechanism by which Srx plays its role in tumor progression and metastasis is not well defined. Early studies have indicated a role of Srx in controlling the phosphorylation status of key regulatory kinases through effects upon phosphatase activity with an ultimate impact on pathways that influence cancer cell proliferation. Srx overexpression triggers altered expression and phosphorylation of cell cycle regulators p21, p27, and p53 and stabilizes the phosphatase PTEN. Srx interacts directly with, and enhanced the activity of, phosphatase PTP1B. In turn, this promotes Src kinase activity by dephosphorylating its inhibitory tyrosine residue (Tyr530) (Lei et al. 2008). Consistently, in another study, Srx was shown to promote tumor progression in lung cancer by enhancing intracellular phosphokinase signaling such as mitogen-activated protein kinase (MAPK) and AP-1/MMP9 (matrix metalloproteinase 9) (Wei et al. 2011). In addition, Srx has been demonstrated to form a complex with S100A4 and non-muscle myosin (NMIIA); promote S100A4 and NMIIA interaction, possibly through deglutathionylation of NMIIA; and lead to dissociation of the NMIIA filaments halting the retrograde flow and in this way promoting lung cancer cell protrusiveness and migration (Bowers et al. 2012). Furthermore, Srx has been shown to promote colorectal cancer cell invasion and metastasis through activation of EGFR signaling as a result of its inhibition of EGFR acetylation at K1037 (Jiang et al. 2015).
Sulfiredoxin is a ubiquitous and highly expressed redox active protein that participates in a number of pathways critical in regulating cell fate following exposure to oxidative or nitrosative stress. Its capacity to regenerate peroxiredoxins and to modulate posttranslational modifications of cysteine-containing proteins implies that its aberrant expression patterns in many cancers are likely linked with the altered redox homeostatic parameters found in this disease. Early attempts to interfere with sulfiredoxin will progress in a manner that may lead to therapeutic utility in managing cancer.
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