Redox signaling is a critical component of cell signaling pathways that is involved in regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Peroxiredoxin (Prx) is a family of thiol-based peroxidases that acts as a regulator of redox signaling. Members of Prx family can act as antioxidants and chaperone. Sulfiredoxin (Srx) is an antioxidant protein that exclusively reduces over-oxidized typical 2-Cys Prx. Srx have different affinities for individual Prx and it also catalyzes deglutathionylation of variety of substrates. Individual components of Srx-Prx system play critical roles in carcinogenesis by modulating cell signaling pathway involved in cell proliferation, migration and metastasis. Expression levels of individual components of Srx-Prx axis has been correlated with patient survival outcome in multiple cancer types. This review will summarize the molecular basis of differences in affinity of Srx for individual Prx and the role of individual components of Srx-Prx system in tumor progression and metastasis. This enhanced understanding of molecular aspects of Srx-Prx interaction and its role in cell signal transduction will help in defining Srx-Prx system as a future therapeutic target in human cancer.

Sulfiredoxin (SRXN1/Srx) is a multifunction enzyme with a primary antioxidant role of reducing the overoxidized inactive form of peroxiredoxins (Prxs). The function and mechanisms of Srx in cancer development are not well understood. Here, Srx is preferentially expressed in human colorectal cancer (CRC) cells but not in normal colon epithelial cells. Loss-of-function studies demonstrate that knockdown of Srx in poorly differentiated CRC 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 CRC cells. Mechanistically, expression of Srx enhances the activation of mitogen activated protein kinase (MAPK) signaling through increasing the C-terminal tyrosine phosphorylation levels of epidermal growth factor receptor (EGFR). This function of Srx is mediated through its inhibition of EGFR acetylation at K1037, a novel post-translational modification of EGFR in human CRC cells identified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) proteomic analysis. Furthermore, abolishment of K1037 acetylation in human CRC cells by site-specific mutagenesis leads to sustained activation of EGFR-MAPK signaling. Combined, these data reveal that Srx promotes CRC cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling. Implications Sulfiredoxin is a critical oncogenic protein that can be used as a molecular target to develop therapeutics for patients with metastatic colorectal cancer.

Sulfiredoxin (Srx), the exclusive enzyme that reduces the hyperoxidized inactive form of peroxiredoxins (Prxs), has been found highly expressed in several types of human skin cancer. To determine whether Srx contributed to skin tumorigenesis in vivo, Srx null mice were generated on an FVB background. Mouse skin tumorigenesis was induced by a 7,12-dimethylbenz[α]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) protocol. We found that the number, volume and size of papillomas in Srx(-/-) mice were significantly fewer compared with either wild-type (Wt) or heterozygous (Het) siblings. Histopathological analysis revealed more apoptotic cells in tumors from Srx(-/-) mice. Mechanistic studies in cell culture revealed that Srx was stimulated by TPA in a redox-independent manner. This effect was mediated transcriptionally through the activation of mitogen-activated protein kinase and Jun-N-terminal kinase. We also demonstrated that Srx was capable of reducing hyperoxidized Prxs to facilitate cell survival under oxidative stress conditions. These findings suggested that loss of Srx protected mice, at least partially, from DMBA/TPA-induced skin tumorigenesis. Therefore, Srx has an oncogenic role in skin tumorigenesis and targeting Srx may provide novel strategies for skin cancer prevention or treatment.

Correct folding of nascent peptides occurs in the endoplasmic reticulum (ER). It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase (PDI) family. As a critical member of the PDI family, thioredoxin domain containing protein 5 (TXNDC5) assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions. Interestingly, TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer. In this review, we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development. Findings of TXNDC5 in the activation of intracellular signaling pathways, stimulation of cell growth & proliferation, facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed. These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.

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Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking and exposure to chemical carcinogens are among the risk factors of lung tumorigenesis. In this study, we found that cigarette smoke condensate and urethane significantly stimulated the expression of sulfiredoxin (Srx) at the transcript and protein levels in cultured normal lung epithelial cells, and such stimulation was mediated through the activation of nuclear related factor 2 (Nrf2). To study the role of Srx in lung cancer development in vivo, mice with Srx wildtype, heterozygous or knockout genotype were subjected to the same protocol of urethane treatment to induce lung tumors. By comparing tumor multiplicity and volume between groups of mice with different genotype, we found that Srx knockout mice had a significantly lower number and smaller size of lung tumors. Mechanistically, we demonstrated that loss of Srx led to a decrease of tumor cell proliferation as well as an increase of tumor cell apoptosis. These data suggest that Srx may have an oncogenic role that contributes to the development of lung cancer in smokers or urethane-exposed human subjects.

<p>Ectopical expression of FlagSrx in HT29 cells promotes the C-terminal tyrosine phosphorylation of EGFR and activates downstream MAPK signaling. Cells were serum starved for overnight and then treated with or without 50 ng/ml of EGF containing medium for indicated times. Results from a single membrane western blot were shown in (A) and quantitative data from three independent experiments were shown in (B). Compared to control cells, * p< 0.05 (paired t test, n = 3).</p>

<p>The layout of the human protein profiler phospho-RTK assay (A) and list of RTKs (B).</p>