Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in Apc Min/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecular Cancer Therapeutics Année : 2008

Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in Apc Min/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways

Kiyoshi Yamaguchi
  • Fonction : Auteur
Maria Cekanova
  • Fonction : Auteur
Michael F Mcentee
  • Fonction : Auteur
Joo-Heon Yoon
  • Fonction : Auteur
Susan M Fischer
  • Fonction : Auteur
Ingrid B Renes
  • Fonction : Auteur
Seung Joon Baek
  • Fonction : Auteur

Résumé

A large body of studies has suggested that peroxisome proliferator-activated receptor ; (PPAR;) ligands, such as thiazolidinedione, are potent candidates for chemopreven-tive agents. MCC-555 is a PPAR;/A 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 PPAR; antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPAR;-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 PPAR; pathways. [Mol Cancer Ther 2008;7(9):2779-87]
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hal-02905848 , version 1 (30-09-2020)

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Kiyoshi Yamaguchi, Maria Cekanova, Michael F Mcentee, Joo-Heon Yoon, Susan M Fischer, et al.. Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in Apc Min/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways. Molecular Cancer Therapeutics, 2008, ⟨10.1158/1535-7163.MCT-08-0173⟩. ⟨hal-02905848⟩

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