PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

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.

Long-term hypoxia exposure enhanced IGFBP-3 protein synthesis and secretion resulting in cell apoptosis in H9c2 myocardial cells

“…Insulin like growth factor binding protein-3 (IGFBP3), the most abundant of the six IGFBPs (Shahjee et al, 2013), is a key mediator of insulin-like growth factor (IGF) biological activity (Firth & Baxter, 2002). Several studies have shown that IGFBP3 could regulate cell proliferation by inducing its anti-proliferative and pro-apoptotic effects in different types of cancer cells (Han et al, 2014;Kim et al, 2015;Shahjee & Bhattacharyya, 2014). However, the IGFBP3 effects on the normal cell were relatively unclear.…”

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“…Also, transactivation of PPARγ lowers the level of angiogenic factors and reduces the migration and proliferation of endothelial cells [249]. The overexpression of PPARγ receptors in SNU-668 gastric cancer cells having adenovirus gene exhibited significant growth inhibition and activation of apoptosis due to strong up-regulation of a tumor suppressor gene, insulin-like growth factor-binding protein-3 [250]. Some workers have shown that the genomic activation of PPARγ by microRNA-125b suppress the expression of B-cell lymphoma 3 protein, a proto-oncogene, thereby reduce the growth of ovarian cancer [251].…”

A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor

“…Adenovirus gene transferred SNU-668 gastric cancer cells with overexpression of PPARγ presented significant the growth inhibition and apoptosis activation due to strong IGFBP-3 upregulation. Insulin-like growth factor-binding protein-3 IGFBP-3 is a tumor suppressor gene, independent of IGF signaling [ 76 ]. Some reports proved that activation of PPARγ can inhibit the growth of ovarian cancer by suppressing proto-oncogene B-cell lymphoma 3-encoded protein (BCL3) in response to microRNA-125b (miR-125b) tumor suppressor upregulation.…”