Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis

Cancer Res. 2009 Jun 1;69(11):4776-83. doi: 10.1158/0008-5472.CAN-08-4754. Epub 2009 May 19.

Abstract

Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma is required for embelin to exert its effect. A dominant-negative PPARgamma was used to antagonize endogenous PPARgamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappaB (NF-kappaB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARgamma(+/+) and PPARgamma(+/-) 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 PPARgamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARgamma. PPARgamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPARgamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPARgamma(+/+) mice but not in PPARgamma(+/-) mice. Embelin inhibited NF-kappaB activity in PPARgamma(+/+) mice but marginally so in PPARgamma(+/-) mice. Thus, reduced expression of PPARgamma 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 PPARgamma, indicating that PPARgamma is a necessary signaling pathway involved in the antitumor activity of normal organisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenocarcinoma / prevention & control
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Benzoquinones / pharmacology*
  • Benzoquinones / therapeutic use
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Colonic Neoplasms / prevention & control
  • Drug Evaluation, Preclinical
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / physiology*
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • NF-kappa B
  • PPAR gamma
  • embelin