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Role of the 15kDa selenoprotein (Sep15) in colon cancer prevention
Author(s) -
Tsuji Petra,
Irons Robert,
Carlson Bradley,
Yoo MinHyuk,
Xu XueMing,
Formenko Dmitri,
Gladyshev Vadim,
Hatfield Dolph,
Davis Cindy
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.218.5
Subject(s) - azoxymethane , gene knockdown , selenoprotein , cancer research , biology , knockout mouse , cell cycle , cancer , carcinogenesis , gene knockout , carcinogen , microbiology and biotechnology , apoptosis , gene , biochemistry , oxidative stress , genetics , superoxide dismutase , glutathione peroxidase
Selenium has cancer preventive activity that is partly mediated through selenoproteins. shRNA knockdown of Sep15 in mouse colon carcinoma CT26 cells inhibited their anchorage‐dependent and ‐independent cell growth, primary tumor growth and lung metastasis. In contrast, Sep15 knockdown in Lewis Lung carcinoma cells did not affect anchorage‐dependent or –independent growth. To investigate molecular targets, mRNA from control and knockdown CT26 cells was analyzed using Affymetrix gene chips. Ingenuity Pathways Analysis was used to analyze the 1045 genes that were significantly (p<0.0001) different between shSep15 and control cells. The two highest scored biological functions were cancer and cellular growth/proliferation. Subsequent FACS analysis confirmed a G2/M cell cycle arrest in shSep15 knockdown cells. To investigate the effect of Sep15 knockout in vivo, mice were treated with azoxymethane. Sep15 knockout mice had significantly fewer carcinogen‐induced aberrant crypt foci in their colon than control mice. These data suggest tissue specificity in the cancer protective effects of Sep15, which are mediated, at least in part, by influencing cell cycle. Furthermore, Sep15 knockout mice appear to be protected against chemically‐induced colon cancer. Funded by NCI Intramural support, the Cancer Prevention Fellowship Program and the Division of Cancer Prevention.