title: Peroxisome proliferator-activated receptor gamma-dependent and -independent growth inhibition of gastrointestinal tumour cells.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a ligand-activated transcription factor. Although ligand-induced cellular differentiation and growth inhibition have been mostly studied on human cancers expressing PPARgamma, it is unclear if the transcriptional activation of PPARgamma is the main mechanism of growth inhibition. In this study, we investigated whether there is a link between growth inhibitory effect and transcriptional activation of PPARgamma in several gastrointestinal tumour cell lines. The transcriptional activation potential of PPARgamma was assessed by reporter gene assay employing a PPRE-luciferase vector, and growth inhibitory effect of PPARgamma was investigated by (3)H-thymidine incorporation assay, in the presence or absence of thiazolidinedione ligands, rosiglitazone and troglitazone. As expected, in the case of cell lines positive for the transcriptional activation potential of PPARgamma (T.Tn, MKN-45 and LoVo), both the ligands induced growth inhibition. However, in case of some other cell lines negative for the transcriptional activation potential of PPARgamma (TT, AGS and HCT-15), troglitazone still showed a growth inhibitory effect. Administration of the PPARgamma antagonist GW9662 did not reverse this growth inhibitory activity of troglitazone. The introduction of dominant negative mutants of PPARgamma did not suppress the activity either. These observations suggest that while rosiglitazone inhibits cellular growth predominantly through transcriptional activation of PPARgamma, troglitazone can induce it both in PPARgamma-dependent and -independent pathways.
authors.affiliation: Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo-City, Shimane 693-8501, Japan.
authors.forename: M Azharul Karim
authors.initials: MA
authors.lastname: Rumi
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishihara
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kadowaki
authors.forename: C F
authors.initials: CF
authors.lastname: Ortega-Cava
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kazumori
authors.forename: Kousaku
authors.initials: K
authors.lastname: Kawashima
authors.forename: Nagisa
authors.initials: N
authors.lastname: Yoshino
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yuki
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishimura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D001483:Base Sequence; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary; D004789:Enzyme Activation; D005770:Gastrointestinal Neoplasms / Q000473:pathology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D047495:PPAR gamma; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3