GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells.
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.
Banning
Antje
A
German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Florian
Simone
S
Deubel
Stefanie
S
Thalmann
Sophie
S
Müller-Schmehl
Katrin
K
Jacobasch
Gisela
G
Brigelius-Flohé
Regina
R
D015153:Blotting, Western; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007375:Interleukin-1; D034741:RNA, Small Interfering; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone