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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

 Kiyoshi Yamaguchi  ;  Maria Cekanova  ;  Michael F. McEntee  ;  Joo-Heon Yoon  ;  Susan M. Fischer  ;  Ingrid B. Renes  ;  Isabelle Van Seuningen  ;  Seung Joon Ba다 
 MOLECULAR CANCER THERAPEUTICS, Vol.7(9) : 2779-2787, 2008 
Journal Title
Issue Date
Adenomatous Polyposis Coli Protein/deficiency* ; Animals ; Cell Line, Tumor ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Intestinal Polyps/enzymology* ; Intestinal Polyps/pathology* ; Ligands ; Lung Neoplasms/genetics ; Mice ; Mice, Inbred C57BL ; Mucin-2 ; Mucins/genetics ; Mucins/metabolism ; Peroxisome Proliferator-Activated Receptors/metabolism* ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Thiazolidinediones/chemistry ; Thiazolidinediones/pharmacology* ; Transcription, Genetic/drug effects
MCC-555 ; colorectal cancer ; ApcMin/+ mice ; MUC2 ; PPARs ; ERK pathway
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
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Yoon, Joo Heon(윤주헌)
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