Peroxisome Proliferator-Activated Receptor γ (PPARγ) Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the β-Catenin / T Cell Factor (TCF) Pathway
| Autor: | Ayako Tomimoto, Atsushi Nakajima, Kyoko Yonemitsu, Naoto Kubota, Toshio Fujisawa, Noriko Nakajima, Richard S. Blumberg, Hitoshi Nakagama, Chiho Kudo, Takashi Kadowaki, Yasuo Terauchi, Ikuko Ikeda, Nobutaka Fujisawa, Hirokazu Takahashi, Koichiro Wada |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Time Factors Colon Active Transport Cell Nucleus Azoxymethane Peroxisome proliferator-activated receptor Biology Transfection medicine.disease_cause Mice Internal medicine medicine Animals Humans Receptor beta Catenin Cell Proliferation Mice Knockout Pharmacology chemistry.chemical_classification Mice Inbred BALB C Pioglitazone Cell growth lcsh:RM1-950 Epithelial Cells digestive system diseases PPAR gamma Cell Transformation Neoplastic lcsh:Therapeutics. Pharmacology Endocrinology chemistry Nuclear receptor Catenin Colonic Neoplasms Cancer research Molecular Medicine Female RNA Interference Thiazolidinediones Caco-2 Cells Signal transduction TCF Transcription Factors Carcinogenesis HT29 Cells Protein Binding Signal Transduction Aberrant crypt foci |
| Zdroj: | Journal of Pharmacological Sciences, Vol 106, Iss 4, Pp 627-638 (2008) |
| ISSN: | 1347-8648 1347-8613 |
| DOI: | 10.1254/jphs.fp0071766 |
| Popis: | Peroxisome proliferator-activated receptor γ (PPARγ ), a nuclear receptor superfamily member, plays a major role in lipid metabolism and insulin sensitivity. We investigated the role of PPARγ in colonic epithelial cell turnover and carcinogenesis in colon because PPARγ is strongly expressed in colonic epithelium. Administration of PPARγ agonists suppressed epithelial cell turnover in mice. Expression level of β-catenin protein, a key molecule in carcinogenesis, was increased in mouse colon treated with PPARγ ligands. A direct interaction between β-catenin and PPARγ in cultured cell lines and colonic epithelium in mice was observed. Ligand-activated PPARγ ligand directly interacts with β-catenin, retaining it in the cytosol and reducing β-catenin / T cell factor (TCF) transcriptional activity that is functionally important on aberrant crypt foci (ACF) formation. PPARγ hetero-deficiency promoted the induction of ACF, but had no effect on the incidence of colonic polyps. These results indicate that PPARγ regulates colonic epithelial cell turnover via direct interactions with β-catenin, resulting in inhibition of β-catenin–mediated transcriptional pathways that are involved in promoting cell proliferation. Our findings suggest that PPARγ plays a role as a physiological regulator of colonic epithelial cell turnover and consequently predisposition to the development of colon cancer in early stage. Keywords:: peroxisome proliferator-activated receptor γ (PPARγ ), epithelial cell turnover, β-catenin, colon cancer |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|