title: Dickkopf 3 attenuates xanthine dehydrogenase expression to prevent oxidative stress-induced apoptosis.
abstract: Dickkopf (DKK) 3 is a DKK glycoprotein family member that controls cell fate during embryogenesis and exerts opposing effects on survival in a cell type-dependent manner; however, the mechanisms governing its pro-apoptosis versus pro-survival functions remain unclear. Here, we investigated DKK3 function in Li21 hepatoma cells and tPH5CH immortalized hepatocytes. DKK3 knockdown by siRNA resulted in reactive oxygen species accumulation and subsequent apoptosis, which were abrogated by administration of the antioxidant N-acetyl-cysteine. Moreover, forced DKK3 over-expression induced resistance to hydrogen peroxide (H2O2)-induced apoptosis. Expression analysis by cDNA microarray showed that xanthine dehydrogenase (XDH) expression was significantly lower in Li21 and tPH5CHDKK3-over-expressing cells in response to H2O2treatment when compared to that in their respective mock-transfected controls, whereas a marked increase was observed in H2O2-treated DKK3 knockdown cells. Thus, these data suggest that DKK3 promotes cell survival during oxidative stress by suppressing the expression of the superoxide-producing enzyme XDH.
authors.affiliation: Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qui
authors.affiliation: Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Junko
authors.identifier: http://orcid.org/0000-0003-2313-2324
authors.initials: J
authors.lastname: Kano
authors.affiliation: Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Noguchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D018925:Chemokines; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D018384:Oxidative Stress; D014968:Xanthine Dehydrogenase / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D006861:Hydrogen Peroxide; D014968:Xanthine Dehydrogenase