Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development

Mike Mueller, Simone Florian, Stefanie Pommer, Martin Osterhoff, R Steven Esworthy, Fong-Fong Chu, Regina Brigelius-Flohé, Anna P Kipp

Research output: Contribution to journalArticlepeer-review

Abstract

The selenoprotein glutathione peroxidase-2 (GPx2) appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment), it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only). GPx2-knockout (KO) and wild-type (WT) mice were adjusted to an either marginally deficient (-Se), adequate (+Se), or supranutritional (++Se) selenium status and were treated six times with azoxymethane (AOM) to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.

Original languageEnglish
Pages (from-to)e72055
JournalPLoS ONE
Volume8
Issue number8
DOIs
Publication statusPublished - 2013

Keywords

  • Adenoma
  • Animals
  • Antioxidants
  • Apoptosis
  • Azoxymethane
  • Carcinogenesis
  • Colonic Neoplasms
  • Diet
  • Dietary Supplements
  • Epithelial Cells
  • Gene Deletion
  • Glutathione Peroxidase
  • Humans
  • Intestinal Mucosa
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Precancerous Conditions
  • Proliferating Cell Nuclear Antigen
  • Selenium
  • beta Catenin

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