PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells

✍ Scribed by Shinji Kitamura; Yoshiji Miyazaki; Shintaro Hiraoka; Yutaka Nagasawa; Miyuki Toyota; Rena Takakura; Tatsuya Kiyohara; Yasuhisa Shinomura; Yuji Matsuzawa

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: French
• Weight: 265 KB
• Volume: 94
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.1470

✦ Synopsis

Peroxisome proliferator-activated receptor ␥ (PPAR␥) inhibits the growth of several types of cancer cells. However, the mechanisms by which this occurs are poorly understood. The goal of the present study was to investigate the effects of PPAR␥ on mutated ras-induced cell growth, activation of transcription factors and expression of genes associated with cellular transformation in rat intestinal epithelial cells. A human PPAR␥ cDNA was introduced to the activated H-rastransfected IEC-6 cells (IECras) and 1 clone (IECrasPR82) that stably expresses both activated ras and PPAR␥ was obtained. Thiazolidinedione derivatives such as troglitazone and rosiglitazone, selective ligands for PPAR␥, inhibited the cellular growth of IECrasPR82 cells in a time-dependent manner and induced G1 cell cycle arrest. Treatment with troglitazone (20 M) decreased the expression of cyclin D1, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and amphiregulin and suppressed the promoter activities of cyclin D1 and HB-EGF. Furthermore, a luciferase assay and an electrophoretic mobility shift assay showed that thiazolidinedione derivatives suppressed the transcriptional activities of AP-1 and Ets, both of which play crucial roles in the expression of cyclin D1 and HB-EGF. These findings suggest that reduction of EGF-like growth factors and cyclin D1 through the suppression of AP-1 and Ets may be 1 mechanism whereby PPAR␥ inhibits their growth.