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
S. Kitamura et al., 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, INT J CANC, 94(3), 2001, pp. 335-342
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.