The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-g (PPARg) and thiazolidinedione- PPARg agonists
نویسندگان
چکیده
The peroxisome proliferator-activated receptor-g (PPARg) is a member of the nuclear hormone receptor superfamily. Ligand activation of PPARg is associated with differentiation and inhibition of proliferation in the normal and malignant cells. Herein, we studied the effects of PPARg and the PPARg agonists thiazolidinediones (TZDs) on the insulin receptor (IR), a cell membrane tyrosine kinase receptor protein, whose role is of paramount importance in mediating the metabolic and growth-promoting effects of the peptide hormone insulin. Overexpression of the PPARg1 in human hepatocellular (HepG2) cells was associated with decreased IR gene transcription and protein expression levels, and these reductions were more evident in the presence of TZDs. Since no PPARg response elements were identified on the IR promoter, we postulated that PPARg adversely affects the IR gene transcription by perturbing the assembly and stability of the transcriptionally active multiprotein-DNA complex identified previously, which includes the high-mobility group A1 protein, the ubiquitously expressed transcription factor (Sp1), the CAAT enhancer-binding protein (C/EBPb), and, in some cell lines, the developmentally regulated activator protein-2 (AP-2) transcription factor. Using glutathione S-transferase pull-down assays combined with electrophoretic mobility shift assay and chromatin immunoprecipitation, we demonstrated that by interacting with Sp1, C/EBPb, and AP-2, PPARg can prevent Sp1/AP-2 protein–protein association and inhibit binding of Sp1 and C/EBPb to DNA, thus reducing IR gene transcription. Our results demonstrate that IR is a new target gene of PPARg, and support a potential use of TZDs as anti-proliferative agents in selected neoplastic tissues overexpressing IRs. Endocrine-Related Cancer (2008) 15 325–335
منابع مشابه
Case-control study on peroxisome proliferator-activated receptor gamma polymorphism and interaction with HDL on essential hypertension in Chinese Han
Objective(s): To investigate the association of single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors gamma (PPARG) with essential hypertension (EH) and additional role of gene– high-density lipoprotein cholesterol (HDL) interaction. Materials and Methods:A total of 1640 patients with EH (806 males, 834 females), with a mean age of 52.5±12.6 years, were selec...
متن کاملTroglitazone Reduces the Expression of PPARg While Stimulating That of PPARa in Mononuclear Cells in Obese Subjects*
We have recently demonstrated that troglitazone exerts an antiinflammatory effect in the insulin resistant obese in vivo in parallel with its insulin-sensitizing effect. Because these effects are thought to be mediated through peroxisome proliferator-activated receptors a and g (PPARa and PPARg), we have now examined the possibility that troglitazone may modulate the expression of PPARa and PPA...
متن کاملChem. Pharm. Bull. 55(7) 1053—1059 (2007)
PPARg and PPARd) are a set of ligand-activated transcription factors in the nuclear hormone receptor superfamily. These receptors regulate the expression of a large number of genes involved in lipid metabolism and energy balance by binding to a DNA sequence termed PPAR response elements. The PPARg is predominantly expressed in adipose tissues, and plays a pivotal role in adipose differentiation...
متن کاملEffects of peroxisome proliferator-activated receptor-gamma (PPAR-g) agonists and physical activity on long-term stroke outcome in a mouse model
متن کامل
Circulating free fatty acids are increased independently of PPARg activity after administration of poloxamer 407 to mice
Poloxamer 407 (P-407) is a copolymer surfactant that induces a dose-controlled dyslipidemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentration-dependent reduction in cholesterol efflux to apolipoprotein A1 (apoA1) linked to downregulation of the ATP-binding cassette transporter A1 (ABCA1). Activators of peroxisome proliferator-activated receptor gamma (PPARg), ...
متن کامل