title: Glutathione peroxidase-2 and selenium decreased inflammation and tumors in a mouse model of inflammation-associated carcinogenesis whereas sulforaphane effects differed with selenium supply.
abstract: Chronic inflammation and selenium deficiency are considered as risk factors for colon cancer. The protective effect of selenium might be mediated by specific selenoproteins, such as glutathione peroxidases (GPx). GPx-1 and -2 double knockout, but not single knockout mice, spontaneously develop ileocolitis and intestinal cancer. Since GPx2 is induced by the chemopreventive sulforaphane (SFN) via the nuclear factor E2-related factor 2 (Nrf2)/Keap1 system, the susceptibility of GPx2-KO and wild-type (WT) mice to azoxymethane and dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis was tested under different selenium states and SFN applications. WT and GPx2-KO mice were grown on a selenium-poor, -adequate or -supranutritional diet. SFN application started either 1 week before (SFN4) or along with (SFN3) a single AOM application followed by DSS treatment for 1 week. Mice were assessed 3 weeks after AOM for colitis and Nrf2 target gene expression and after 12 weeks for tumorigenesis. NAD(P)H:quinone oxidoreductases, thioredoxin reductases and glutathione-S-transferases were upregulated in the ileum and/or colon by SFN, as was GPx2 in WT mice. Inflammation scores were more severe in GPx2-KO mice and highest in selenium-poor groups. Inflammation was enhanced by SFN4 in both genotypes under selenium restriction but decreased in selenium adequacy. Total tumor numbers were higher in GPx2-KO mice but diminished by increasing selenium in both genotypes. SFN3 reduced inflammation and tumor multiplicity in both Se-adequate genotypes. Tumor size was smaller in Se-poor GPx2-KO mice. It is concluded that GPx2, although supporting tumor growth, inhibits inflammation-mediated tumorigenesis, but the protective effect of selenium does not strictly depend on GPx2 expression. Similarly, SFN requires selenium but not GPx2 for being protective.
authors.affiliation: Department of Biochemistry of Micronutrients, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Krehl
authors.forename: Maria
authors.initials: M
authors.lastname: Loewinger
authors.forename: Simone
authors.initials: S
authors.lastname: Florian
authors.forename: Anna P
authors.initials: AP
authors.lastname: Kipp
authors.forename: Antje
authors.initials: A
authors.lastname: Banning
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
authors.forename: Martin N
authors.initials: MN
authors.lastname: Brauer
authors.forename: Renato
authors.initials: R
authors.lastname: Iori
authors.forename: Robert S
authors.initials: RS
authors.lastname: Esworthy
authors.forename: Fong-Fong
authors.initials: FF
authors.lastname: Chu
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohé
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D003092:Colitis / Q000139:chemically induced / Q000235:genetics; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D016264:Dextran Sulfate / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis; D007082:Ileum / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy*; D017879:Isothiocyanates; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis; D012643:Selenium / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000096:biosynthesis
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D013861:Thiocyanates; D016264:Dextran Sulfate; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D016660:NAD(P)H Dehydrogenase (Quinone); D013880:Thioredoxin-Disulfide Reductase; D005982:Glutathione Transferase; C016766:sulforaphane; D012643:Selenium; D001397:Azoxymethane