Abstract
Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are multifunctional nuclear hormone receptors that influence cell growth, cell differentiation, and cell death [1]
Robust expression of Peroxisome proliferator activator receptor-gamma (PPARc) was observed after 2 days (Figure 1A) and was coincident with marked inhibition of cell growth and reduction of cell numbers compared with the initial numbers (Figure 1B)
The active enzyme was present in Ad/PPARc-transduced cells, but not in mock-transduced control or Ad/LacZ-transduced cells, indicating that PPARc over-expression provides a stimulus for induction of apoptosis, and that the marked inhibitory effect on tumor cell growth by PPARc is related to its ability to induce apoptosis
Summary
Peroxisome proliferator-activated receptors (PPARs) are multifunctional nuclear hormone receptors that influence cell growth, cell differentiation, and cell death [1]. There are three PPAR isoforms, PPARa, PPARb/d, and PPARc, and of these, PPARc is mainly expressed in adipose tissues. It regulates lipid and glucose metabolism and adipocyte differentiation [2]. One mechanism by which PPARc exerts its effects is by increasing the expression of proteins involved in apoptosis and regulation of cell growth, such as Bax (BCL2-associated X), Bid (BH3 interacting-domain), tumor suppressor p53 [6], and the cyclin-dependent kinase inhibitor (CDKI) p21 [7]. PPARc ligands have been shown to suppress angiogenesis by inhibiting vascular endothelial growth factor (VEGF)receptor 2 expression and blocking VEGF-receptor signaling [8]. PPARc agonists such as troglitazone and ciglitazone inhibit metastasis by inhibiting migration of vascular endothelial cells [9]
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Schedule a callMore From: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
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