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

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) inhibits the growth of several types of cancer cells. However, the mechanisms by which t his occurs are poorly understood. The goal of the present study was to inve stigate the effects of PPAR gamma on mutated ras-induced cell growth, activ ation of transcription factors and expression of genes associated with cell ular transformation in rat intestinal epithelial cells. A human PPAR gamma cDNA was introduced to the activated H-ras-transfected IEC-6 cells (IECras) and 1 clone (IECrasPR82) that stably expresses both activated ras and PPAR -gamma was obtained. Thiazolidinedione derivatives such as troglitazone and rosiglitazone, selective ligands for PPAR gamma, inhibited the cellular gr owth of IECrasPR82 cells in a time-dependent manner and induced G1 cell cyc le arrest. Treatment with troglitazone (20 muM) 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 a nd HB-EGF. Furthermore, a luciferase assay and an electrophoretic mobility shift assay showed that thiazolidinedione derivatives suppressed the transc riptional activities of AP-1 and Ets, both of which play crucial roles in t he expression of cyclin D1 and HB-EGF. These findings suggest that reductio n of EGF-like growth factors and cyclin D1 through the suppression of AP-1 and Ets may be 1 mechanism whereby PPAR gamma inhibits their growth. (C) 20 01 Wiley-Liss, Inc.