Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN

Abstract

The PTEN tumor suppressor gene modulates several cellular functions, including cell migration, survival, and proliferation [1] by antagonizing phosphatidylinositol 3-kinase (PI 3-kinase)-mediated signaling cascades. Mechanisms by which the expression of PTEN is regulated are, however, unclear. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) [2] has been shown to regulate differentiation and/or cell growth in a number of cell types [3, 4, 5], which has led to the suggestion that PPARgamma, like PTEN [1, 6], could act as a tumor suppressor. PPARgamma has also been implicated in anti-inflammatory responses [7, 8], although downstream mediators of these effects are not well defined. Here, we show that the activation of PPARgamma by its selective ligand, rosiglitazone, upregulates PTEN expression in human macrophages, Caco2 colorectal cancer cells, and MCF7 breast cancer cells. This upregulation correlated with decreased PI 3-kinase activity as measured by reduced phosphorylation of protein kinase B. One consequence of this was that rosiglitazone treatment reduced the proliferation rate of Caco2 and MCF7 cells. Antisense-mediated disruption of PPARgamma expression prevented the upregulation of PTEN that normally accompanies monocyte differentiation and reduced the proportion of macrophages undergoing apoptosis, while electrophoretic mobility shift assays showed that PPARgamma is able to bind two response elements in the genomic sequence upstream of PTEN. Our results demonstrate a role for PPARgamma in regulating PI 3-kinase signaling by modulating PTEN expression in inflammatory and tumor-derived cells.

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

“…36 Prior studies, which tested Rosi's ability to induce PTEN in MCF-7 cells, studied its effect at only 1 dose, 1 lM. 18 Studying Rosi's effects on PTEN at 1 dose limits one's ability to detect a potentially more significant dose effect. We, therefore, determined the optimal concentration for increased PTEN expression, by studying our agonists in a dose curve.…”

“…17 In 2001, 2 putative binding sites for the transcription factor peroxisome proliferator-activated receptor-gamma (PPARg) were identified about 10 kb upstream of the minimal promoter region of PTEN. 18 However, the biological importance of these sites and what role PPARg plays in PTEN transcription has not been determined. Therefore it remains to be determined if PPARg has a role in PTEN transcription, and if so, which regions of the PTEN promoter are responsible.…”

“…However, recent evidence indicates that PPARg may also act as a tumor suppressor by mediating the transcription of genes necessary for antiproliferation and prodifferentiation, which ultimately can downregulate cellular growth and upregulate apoptosis. 17,18 Increasing evidence has also shown that PPARg activation can be anticarcinogenic, indicating the treatment potential for PPARg agonists in several diseases. 19,20 Furthermore, the addition of PPARg agonists to breast cancer cell lines have been shown to cause them to differentiate.…”

Roles of PTEN (Phosphatase and Tensin Homolog) in Gastric Cancer Development and Progression

“…Studies have shown that the expression and enzymatic DOI:http://dx.doi.org/10.7314/APJCP.2014.15.1.17 Roles of PTEN (Phosphatase and Tensin Homolog) in Gastric Cancer activity of PTEN can be regulated at transcriptional, microRNA (miRNA), and post-translational levels. Positive regulators of PTEN gene expression include, EGR1 (early growth response protein 1), PPARγ (peroxisome proliferator-activated receptor γ) and Tp53 (tumor protein 53; also known as p53); these were shown to directly bind to the PTEN promoter region (Patel et al, 2001;Stambolic et al, 2001;Virolle et al, 2001;Martelli et al, 2011). Negative regulators include MKK-4 (mitogen activated protein kinase kinase-4), TGF-β (transforming growth factor beta), NFκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells), transcriptional cofactor c-JUN and oncogene BMI1; these were shown to suppress PTEN expression in several cancer models (Gericke et al, 2006;Lau et al, 2011;Meng et al, 2012).…”

Anti-tumor effects of prostaglandin D2 and its metabolites, 15-deoxy-Δ12, 14-PGJ2, by peroxisome proliferator-activated receptor (PPAR) γ-dependent and -independent pathways.

“…Thus the activated PPARγ exerts an anti-proliferative effect 20) and increases pro-apoptotic effect by positively regulation of Fas ligand expression 21) . Moreover, PPARγ activation by 15d-PGJ 2 inhibits the activities of the transcriptional factors AP-1, STAT and NFκB 22) , and at least three important genes including the VEGF receptors 1 (Flt-1), 2 (Flk/KDR) and the urokinase plasminogen activator (uPA) during the angiogenic process 23) .…”