A study of sulfiredoxin in colorectal cancer development

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Sulfiredoxin (Srx) is a novel redox regulator whose oxidoreductase activity restores the peroxidase function of the hyperoxidized Peroxiredoxins. We demonstrate that Srx is preferentially expressed in tumor specimens of colorectal cancer (CRC) patients as well as poorly differentiated, CRC-derived malignant cell lines. Knockdown of Srx in malignant CRC cells not only leads to the inhibition of colony formation and cell invasion in vitro, but also abolishes their ability to form metastasis in distal organs in vivo; whereas exactly opposite effects are observed when Srx is ectopically expressed in CRC cells that do not express endogenous Srx. In addition, genomic depletion of Srx in mice renders resistant to carcinogen-induced colorectal tumorigenesis. While the significance of Srx in CRC development is being gradually revealed, the in-depth molecular mechanism of Srx function has not been fully understood and the value of targeting Srx in CRC therapeutics has yet to be determined. We propose that Srx activates specific intracellular signaling pathways and mediates a gene expression signature that facilitates CRC cell invasion and metastasis; and targeted inhibition of Srx oxidoreductase activity may provide novel strategies for CRC prevention and treatment. Our specific aims are: (1) To determine the mechanism by which Srx activates the mitogen activated protein kinase (MAPK) cascade, which involves a novel post-translational modification of the epithelial growth factor receptor (EGFR); (2) to validate Srx-associated gene expression changes and to study how changes in ZEB1 and fascin contribute to CRC cell malignancy; (3) to test the efficacy of a newly-identified-small-molecule inhibitor of Srx in blocking CRC cell tumorigenesis and metastasis in mouse models.
Effective start/end date7/1/1712/31/22


  • American Cancer Society: $792,000.00


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