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.

GPx2 Suppression of H2O2 Stress Links the Formation of Differentiated Tumor Mass to Metastatic Capacity in Colorectal Cancer

“…GPx2 may suppress inflammation by inhibiting cyclooxygenase-2 (COX-2) expression or activity (16,31). Interestingly, although tumor multiplicity was higher in the GPx2-knockout mice, presumably due to more severe inflammation, tumor size was significantly smaller (42). This is consistent with a model in which GPx2 prevents colon tumor initiation by limiting inflammation, but promotes the growth of established tumors by stimulating the formation of differentiated tumor mass (this report).…”

“…The restoration of one GPx2 (but not GPx1) allele almost fully rescued these phenotypes (41). Furthermore, GPx2-knockout mice show severe inflammation and an increased number of tumors in a mouse model for inflammation-triggered colon cancer (42). GPx2 may suppress inflammation by inhibiting cyclooxygenase-2 (COX-2) expression or activity (16,31).…”

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

“…Gpx2 appears to play a complex role in colon carcinogenesis (114), where it inhibits inflammation-driven tumorigenesis (115), yet promotes growth of xenografted tumors (116). Loss of GPX2 leads to dedifferentiation of cells to a progenitorlike state (117).…”

Toward Understanding Success and Failures in the Use of Selenium for Cancer Prevention

“…Knowledge on modulation of intestinal TrxR by Se intake is still incomplete. Dietary Se supplementation has been reported to increase TrxR activity in ileum and colon of mice (48). Contrarily, rectal TrxR mRNA levels in humans with adequate Se status did not respond to supranutritional Se supply (33).…”