Peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of embelin on colon carcinogenesis

Abstract

Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1, 4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPARγ is required for embelin to exert its effect. A dominant-negative PPARγ was used to antagonize endogenous PPARγ in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-κB (NF-κB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARγ +/+ and PPARγ +/- mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPARγ. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARγ. PPARγ +/- mice were more susceptible to DMH-induced colon carcinogenesis than PPARγ +/+ mice, and embelin significantly reduced the incidence of colon cancer in PPARγ +/+ mice but not in PPARγ +/- mice. Embelin inhibited NF-κB activity in PPARγ +/+ mice but marginally so in PPARγ +/- mice. Thus, reduced expression of PPARγ significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPARγ, indicating that PPARγ is a necessary signaling pathway involved in the antitumor activity of normal organisms. ©2009 American Association for Cancer Research.