期刊
CANCER RESEARCH
卷 69, 期 11, 页码 4776-4783出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-4754
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资金
- Simon K.Y. Lee endowed professorship Research Fund
- Gordon Chiu Stomach Cancer Research Fund
- Outstanding Researcher Award Fund of the University of Hong Kong, Hong Kong
- University of Hong Kong Seed Funding [10206827.49710.20600.302.01]
Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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 PPAR gamma is required for embelin to exert its effect. A dominant-negative PPAR gamma was used to antagonize endogenous PPAR gamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappa B (NF-kappa B) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPAR gamma(+/+) and PPAR gamma(+/-) 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 PPAR gamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPAR gamma. PPAR gamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPAR gamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPAR gamma(+/+) mice but not in PPAR gamma(+/-) mice. Embelin inhibited NF-kappa B activity in PPAR gamma(+/+) mice but marginally so in PPAR gamma(+/-) mice. Thus, reduced expression of PPAR gamma 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 PPAR gamma, indicating that PPAR gamma is a necessary signaling pathway involved in the antitumor activity of norma organisms. [Cancer Res 2009;69(11):4776-83]
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