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.

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.

• Authors: Kiyoshi Yamaguchi, Maria Cekanova, Michael F McEntee, Joo-Heon Yoon, Susan M Fischer, Ingrid B Renes, Isabelle Van Seuningen, Seung Joon Baek
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 9 Pg. 2779-87 (Sep 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18790758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adenomatous Polyposis Coli Protein
• Ligands
• MUC2 protein, human
• Muc2 protein, mouse
• Mucin-2
• Mucins
• Peroxisome Proliferator-Activated Receptors
• RNA, Messenger
• Thiazolidinediones
• Extracellular Signal-Regulated MAP Kinases
• netoglitazone

Topics

• Adenomatous Polyposis Coli Protein (deficiency)
• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (enzymology, genetics, pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intestinal Polyps (enzymology, pathology)
• Ligands
• Lung Neoplasms (genetics)
• Mice
• Mice, Inbred C57BL
• Mucin-2
• Mucins (genetics, metabolism)
• Peroxisome Proliferator-Activated Receptors (metabolism)
• RNA, Messenger (genetics, metabolism)
• Thiazolidinediones (chemistry, pharmacology)
• Transcription, Genetic (drug effects)