Peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the beta-catenin/T cell factor (TCF) pathway.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, plays a major role in lipid metabolism and insulin sensitivity. We investigated the role of PPARgamma in colonic epithelial cell turnover and carcinogenesis in colon because PPARgamma is strongly expressed in colonic epithelium. Administration of PPARgamma agonists suppressed epithelial cell turnover in mice. Expression level of beta-catenin protein, a key molecule in carcinogenesis, was increased in mouse colon treated with PPARgamma ligands. A direct interaction between beta-catenin and PPARgamma in cultured cell lines and colonic epithelium in mice was observed. Ligand-activated PPARgamma ligand directly interacts with beta-catenin, retaining it in the cytosol and reducing beta-catenin/T cell factor (TCF) transcriptional activity that is functionally important on aberrant crypt foci (ACF) formation. PPARgamma hetero-deficiency promoted the induction of ACF, but had no effect on the incidence of colonic polyps. These results indicate that PPARgamma regulates colonic epithelial cell turnover via direct interactions with beta-catenin, resulting in inhibition of beta-catenin-mediated transcriptional pathways that are involved in promoting cell proliferation. Our findings suggest that PPARgamma plays a role as a physiological regulator of colonic epithelial cell turnover and consequently predisposition to the development of colon cancer in early stage.
Fujisawa
Toshio
T
Division of Gastroenterology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan.
Nakajima
Atsushi
A
Fujisawa
Nobutaka
N
Takahashi
Hirokazu
H
Ikeda
Ikuko
I
Tomimoto
Ayako
A
Yonemitsu
Kyoko
K
Nakajima
Noriko
N
Kudo
Chiho
C
Wada
Koichiro
K
Kubota
Naoto
N
Terauchi
Yasuo
Y
Kadowaki
Takashi
T
Nakagama
Hitoshi
H
Blumberg
Richard S
RS
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001397:Azoxymethane; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D047495:PPAR gamma; D051820:TCF Transcription Factors; D045162:Thiazolidinediones; D051176:beta Catenin; D001397:Azoxymethane; D000077205:Pioglitazone