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

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.

• 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)

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

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