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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Authors | Antje Banning, Simone Florian, Stefanie Deubel, Sophie Thalmann, Katrin Müller-Schmehl, Gisela Jacobasch, Regina Brigelius-Flohé |
Journal | Antioxidants & redox signaling
(Antioxid Redox Signal)
Vol. 10
Issue 9
Pg. 1491-500
(Sep 2008)
ISSN: 1557-7716 [Electronic] United States |
PMID | 18479189
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interleukin-1
- RNA, Small Interfering
- GPX2 protein, human
- Glutathione Peroxidase
- Cyclooxygenase 2
- Intramolecular Oxidoreductases
- PTGES protein, human
- Prostaglandin-E Synthases
- Ptges protein, mouse
- Dinoprostone
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Topics |
- Blotting, Western
- Cell Line, Tumor
- Colitis, Ulcerative
(metabolism, pathology)
- Colorectal Neoplasms
(genetics, metabolism, pathology)
- Cyclooxygenase 2
(genetics, metabolism)
- Dinoprostone
(biosynthesis)
- Gene Expression Regulation, Neoplastic
- Glutathione Peroxidase
(genetics, metabolism)
- Humans
- Immunoassay
- Immunohistochemistry
- Interleukin-1
(pharmacology)
- Intramolecular Oxidoreductases
(genetics, metabolism)
- Prostaglandin-E Synthases
- RNA Interference
- RNA, Small Interfering
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
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