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

University of Cambridge, Cambridge, England, United Kingdom
International Journal of Cancer (Impact Factor: 5.09). 05/2006; 118(10):2390-8. DOI: 10.1002/ijc.21799
Source: PubMed


Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease.

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Available from: Kristin A Waite, Mar 23, 2015
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    • "However, PPARγ agonists also diminish activation of Akt-1 in 3T3-L1 adipocyte apoptosis without affecting PI3K and PTEN [49]. Rosiglitazone-induced PTEN expression is accompanied by a decline in activations of Akt and MAPK and a rise in G1 arrest in MCF-7 cells [26, 50]. In our study, rosiglitazone caused G1 arrest and lowered proportion of cells in S+G2M phase, which resulted in growth inhibition in PTEN-deficient cells. "
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    ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR γ ) agonist has anti-inflammatory and anticancer properties. However, the mechanisms by which PPAR γ agonist rosiglitazone interferes with inflammation and cancer via phosphatase and tensin homolog-(PTEN)-dependent pathway remain unclear. We found that lower doses (<25 μM) of rosiglitazone significantly inhibited lipopolysaccharide-(LPS)-induced nitric oxide (NO) release (via inducible nitric oxide synthase, iNOS), prostaglandin E2 (PGE2) production (via cyclooxygenase-2, COX-2), and activation of Akt in RAW 264.7 murine macrophages. However, rosiglitazone did not inhibit the production of reactive oxygen species (ROS). In PTEN knockdown (shPTEN) cells exposed to LPS, rosiglitazone did not inhibit NO release, PGE2 production, and activation of Akt. These cells had elevated basal levels of iNOS, COX-2, and ROS. However, higher doses (25–100 μM) of rosiglitazone, without LPS stimulation, did not block NO release and PGE2 productions, but they inhibited p38 MAPK phosphorylation and blocked ROS generation in shPTEN cells. In addition, rosiglitazone caused G1 arrest and reduced the number of cells in S + G2/M phase, leading to growth inhibition. These results indicate that the anti-inflammatory property of rosiglitazone is related to regulation of PTEN independent of inhibition on ROS production. However, rosiglitazone affected the dependence of PTEN-deficient cell growth on ROS.
    Full-text · Article · Mar 2014
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    • "Many of these PPARγ agonists exhibit antiproliferative activities against many types of cancer cells including those of colon, prostate, and breast, suggesting the potential use of these agents in cancer therapy or prevention [16]. Evidence suggests that PPARγ activation leads to the transcriptional suppression of a series of signaling effectors associated with tumorigenesis, including cell cycle regulators (cyclin D1, cyclin E, and cyclin-dependent kinase (CDK) 6) [17], antiapoptotic proteins (Bcl-2 and XIAP) [18], and cyclooxygenase- (COX-) 2 [19], thereby facilitating apoptotic death in cancer cells [20, 21]. Therefore, PPARγ is recognized as a therapeutically relevant target for cancer therapy [22, 23]. "
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    • "Others found that BMP-2 exposure can regulate PTEN protein levels by decreasing PTEN’s association with the degradative pathway [16]. Teresi et al., [17] demonstrated that transcriptional activation of PPARγ by lovastatin or rosiglitazone could increase PTEN expression. Our data, at least in part, is consistent with these and supports that BMP-2 through PPARγ signalling up-regulates PTEN expression that play an important role in anti-proliferation of PASMC. "
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    ABSTRACT: To investigate the role of bone morphogenetic protein 2 (BMP-2) in regulation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and apoptosis of pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Normal human PASMCs were cultured in growth medium (GM) and treated with BMP-2 from 5-80 ng/ml under hypoxia (5% CO(2)+94% N(2)+1% O(2)) for 72 hours. Gene expression of PTEN, AKT-1 and AKT-2 were determined by quantitative RT-PCR (QRT-PCR). Protein expression levels of PTEN, AKT and phosph-AKT (pAKT) were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4, bpV(HOpic) (PTEN inhibitor) and GW9662 (PPARγ antagonist) were used to determine the signalling pathways. Proliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferation rate was achieved at 60 ng/ml concentration under hypoxia (82.2±2.8%). BMP-2 increased PTEN gene expression level, while AKT-1 and AKT-2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. AKT activity significantly reduced in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2. PTEN expression remained unchanged when Smad-4 expression was inhibited by siRNA-Smad-4. bpV(HOpic) and GW9662 (PPARγ inhibitor) inhibited PTEN protein expression and recovered PASMCs proliferation rate. BMP-2 increased PTEN expression under hypoxia in a dose dependent pattern. BMP-2 reduced AKT activity and increased caspase activity of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPARγ signalling pathway, instead of BMP/Smad signalling pathway.
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