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Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways
Molecular Cancer Therapeutics (2008)
  • K Yamaguchi
  • Maria Cekanova
  • Michael F McEntee, University of Tennessee - Knoxville
  • J H Yoon
  • S M Fischer
  • I B Renes
  • I Van Seungnigen
  • Seung J Baek, The University of Tennessee
Abstract

A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARgamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARgamma antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPARgamma-dependent manner. Moreover, MCC-555 increased transcriptional activity of human and mouse MUC2 promoters. Subsequently, treatment with MCC-555 (30 mg/kg/d) for 4 weeks reduced the number of small intestinal polyps to 54.8% of that in control mice. In agreement with in vitro studies, enhanced Muc2 expression was observed in the small intestinal tumors of Min mice treated with MCC-555, suggesting that MUC2 expression may be associated at least in part with the antitumorigenic action of MCC-555. In addition, highly phosphorylated extracellular signal-regulated kinase (ERK) was found in the intestinal tumors of MCC-555-treated Min mice, and inhibition of the ERK pathway by a specific inhibitor markedly suppressed MCC-555-induced Muc2 expression in vitro. Overall, these results indicate that MCC-555 has a potent tumor suppressor activity in intestinal tumorigenesis, likely involving MUC2 up-regulation by ERK and PPARgamma pathways.

Keywords
  • Adenomatous Polyposis Coli Protein deficiency,
  • Animals,
  • Cell Line,
  • Tumor,
  • Colorectal Neoplasms,
  • genetics,
  • Colorectal Neoplasms pathology,
  • Extracellular Signal-Regulated MAP Kinases,
  • Gene Expression Regulation,
  • Neoplastic drug effects,
  • Humans,
  • enzymology,
  • Intestinal Polyps pathology,
  • Ligands,
  • Lung Neoplasms,
  • Mice,
  • Inbred C57BL,
  • Mucin-2,
  • Mucins genetics,
  • Peroxisome Proliferator-Activated Receptors metabolism,
  • RNA,
  • Messenger metabolism,
  • chemistry,
  • Thiazolidinediones,
  • Transcription
Publication Date
September, 2008
Citation Information
K Yamaguchi, Maria Cekanova, Michael F McEntee, J H Yoon, et al.. "Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways" Molecular Cancer Therapeutics Vol. 7 Iss. 9 (2008)
Available at: http://works.bepress.com/maria_cekanova/1/