Sulfiredoxin Promotes Colorectal Cancer Cell Invasion and Metastasis through a Novel Mechanism of Enhancing EGFR Signaling

摘要: Sulfiredoxin (SRXN1/Srx) is a multifunction enzyme with primary antioxidant role of reducing the overoxidized inactive form peroxiredoxins (Prxs). The function and mechanisms Srx in cancer development are not well understood. Here, preferentially expressed human colorectal cells but normal colon epithelial cells. Loss-of-function studies demonstrate that knockdown poorly differentiated only leads to inhibition colony formation cell invasion vitro, also reduces tumor xenograft growth represses metastasis distal organs mouse orthotopic implantation model. Notably, exactly opposite effects were observed gain-of-function experiments when was ectopically well-differentiated Mechanistically, expression enhances activation MAPK signaling through increasing C-terminal tyrosine phosphorylation levels EGFR. This mediated its EGFR acetylation at K1037, novel posttranslational modification identified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI/MS-MS) proteomic analysis. Furthermore, abolishment K1037 site-specific mutagenesis sustained EGFR–MAPK signaling. Combined, these data reveal promotes mechanism enhancing Implications: critical oncogenic protein can be used as molecular target develop therapeutics for patients metastatic cancer. Mol Cancer Res; 13(12); 1554–66. ©2015 AACR.