PPARgamma 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 (PPARgamma) 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 PPARgamma 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 PPARgamma cDNA was introduced to the activated H-ras-transfected IEC-6 cells (IECras) and 1 clone (IECrasPR82) that stably expresses both activated ras and PPARgamma was obtained. Thiazolidinedione derivatives such as troglitazone and rosiglitazone, selective ligands for PPARgamma, inhibited the cellular growth of IECrasPR82 cells in a time-dependent manner and induced G1 cell cycle arrest. Treatment with troglitazone (20 microM) 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 PPARgamma inhibits their growth.
Kitamura
S
S
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. kitamura@imed2.med.osaka-u.ac.jp
Miyazaki
Y
Y
Hiraoka
S
S
Nagasawa
Y
Y
Toyota
M
M
Takakura
R
R
Kiyohara
T
T
Shinomura
Y
Y
Matsuzawa
Y
Y
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007422:Intestines / Q000166:cytology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000077288:Troglitazone; D018631:ras Proteins / Q000378:metabolism*
D002839:Chromans; D018076:DNA, Complementary; D007004:Hypoglycemic Agents; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000077154:Rosiglitazone; D019938:Cyclin D1; D004815:Epidermal Growth Factor; C089946:2,4-thiazolidinedione; D008156:Luciferases; D018631:ras Proteins; D000077288:Troglitazone