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      GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells.

      Antioxidants & Redox Signaling
      Blotting, Western, Cell Line, Tumor, Colitis, Ulcerative, metabolism, pathology, Colorectal Neoplasms, genetics, Cyclooxygenase 2, Dinoprostone, biosynthesis, Gene Expression Regulation, Neoplastic, Glutathione Peroxidase, Humans, Immunoassay, Immunohistochemistry, Interleukin-1, pharmacology, Intramolecular Oxidoreductases, RNA Interference, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction

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          Abstract

          GPx2, the gastrointestinal glutathione peroxidase, is a selenoprotein predominantly expressed in the intestine. An anti-inflammatory and anticarcinogenic potential has been inferred from the development of colitis and intestinal cancer in GPx1 and GPx2 double knockout mice. Further, induction by Nrf2 activators classifies GPx2 as a protective enzyme. In contrast, enhanced COX-2 expression is consistently associated with inflammation. The antagonistic roles and an intriguing co-localization of GPx2 and COX-2 prompted us to investigate their possible mutual regulation. Both enzymes were upregulated in tissues of patients with colorectal cancer and colitis, and co-localized in the endoplasmic reticulum. A stable knockdown of GPx2 in HT-29 cells by siRNA resulted in a high basal and IL-1-induced expression of COX-2 and mPGES-1, enzymes required for the production of the pro-inflammatory PGE(2). Accordingly, si-GPx2 cells released high concentrations of PGE(2). Observed effects were specific for GPx2, since COX-2 and mPGES-1 expression was not affected by selenium-deprivation which resulted in the disappearance of GPx1. It is concluded that GPx2 by compartmentalized removal of hydroperoxides silences COX-2 activity and suppresses PGE(2)-dependent COX-2 expression. Thus, GPx2 may prevent undue responses to inflammatory stimuli and, in consequence, inflammation-driven initiation of carcinogenesis.

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