The PPAR Gamma Agonist Troglitazone Regulates Erk 1/2 Phosphorylation via a PPARγ-Independent, MEK-Dependent Pathway in Human Prostate Cancer Cells

Bolden, Adrienne; Bernard, Lynikka; Jones, Danielle; Akinyeke, Tunde; Stewart, LaMonica V.

doi:10.1155/2012/929052

Cited by 40 publications

(28 citation statements)

References 41 publications

(55 reference statements)

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“…Paradoxically, it appears that PPARG activation using synthetic ligands (at high concentrations) suppresses in vitro growth in LNCaP, DU145, and PC3 prostate cancer cell lines and in vivo s.c. PC3 growth (20,24,25). However, recent evidence suggests these agonists may act via a PPARGindependent manner to induce cell cycle arrest and apoptosis in CaP (24).…”

Section: Discussionmentioning

confidence: 99%

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

Ahmad

Mui

Galbraith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

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Section: Discussionmentioning

confidence: 99%

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

Ahmad

Mui

Galbraith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Though the roles of PPARγ in cancer therapy are debatable, accumulating evidence suggested that activation of PPARγ by agonists exerts an inhibitory effect on cancer cells [32]. For example, PPARγ agonists dramatically reduced cell growth of hepatocellular carcinoma [33], prostate cancer [34], and gastric cancer [35] via regulating the expression and blocking the oncogenic proteins. In our study, we found that PPARγ agonist RGZ had an ability to inhibit proliferation of esophageal cancer cells in time- and dose-dependent manners.…”

Section: Discussionmentioning

confidence: 99%

Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway

Yang

Liu

et al. 2016

Oncotarget

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Although substantial studies on peroxisome proliferator-activated receptor γ (PPARγ) have focused on the mechanisms by which PPARγ regulates glucose and lipid metabolism, recent reports have suggested that PPARγ shows tumorigenic or antitumorigenic effects. The roles and mechanisms of PPARγ activation in esophageal cancer remain unclarified. EC109 and TE10 esophageal cancer cells were treated with 0, 10, 20 and 40 mM of PPARγ agonist rosiglitazone (RGZ) for 24, 48, and 72 h, and the cell viability and apoptosis were detected using methyl thiazolyl tetrazolium (MTT) assay and Flow cytometric (FCM) analysis, respectively. Moreover, the effects of inhibition of PPARγ by antagonist or specific RNA interference on cell viability, apoptosis, the Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways were evaluated. Additionally, the effect of TLR4 signaling on the MAPK pathway, cell viability and apoptosis was assessed. The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARγ. RGZ suppressed the MAPK and TLR4 pathways, and the inhibitory effect could be counteracted by PPARγ antagonist or specific RNA interference. We also suggested that MAPK activation was regulated by the TLR4 pathway and that blocking the TLR4 and MAPK pathways significantly suppressed proliferation and induced apoptosis of esophageal cancer cells. In conclusion, our data suggested that activation of PPARγ suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.

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“…However, this alternative mechanism of action also appears unlikely based on a prior study demonstrating decreased MUC1 expression following treatment of epithelial cells with antioxidants (29). Finally, phosphorylation of ERK1/2 through the TNF-␣ receptor is known to activate MUC1 expression (25,29), and Bolden et al (8) recently demonstrated that treatment of human prostate cancer cells with TGN induced ERK1/2 phosphorylation via a PPAR␥-independent pathway. However, this effect was only observed at relatively high TGN concentrations (40 M) and no effect on ERK1/2 activation was seen at the doses used in the present study (Ͻ 1.0 M).…”

Section: ϫ/ϫ (Iii Iv) Mice Following Inoculation With Pbs Vehicle Comentioning

confidence: 99%

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

Park

Guang

Blanchard

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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MUC1 is a membrane-tethered mucin expressed on the apical surface of epithelial cells. Our previous report (Guang W, Ding H, Czinn SJ, Kim KC, Blanchard TG, Lillehoj EP. J Biol Chem 285: 20547–20557, 2010) demonstrated that expression of MUC1 in AGS gastric epithelial cells limits Helicobacter pylori infection and reduces bacterial-driven IL-8 production. In this study, we identified the peroxisome proliferator-associated receptor-γ (PPARγ) upstream of MUC1 in the anti-inflammatory pathway suppressing H. pylori- and phorbol 12-myristate 13-acetate (PMA)-stimulated IL-8 production. Treatment of AGS cells with H. pylori or PMA increased IL-8 levels in cell culture supernatants compared with cells treated with the respective vehicle controls. Prior small interfering (si)RNA-induced MUC1 silencing further increased H. pylori - and PMA-stimulated IL-8 levels compared with a negative control siRNA. MUC1-expressing AGS cells pretreated with the PPARγ agonist troglitazone (TGN) had reduced H. pylori - and PMA-stimulated IL-8 levels compared with cells treated with H. pylori or PMA alone. However, following MUC1 siRNA knockdown, no differences in IL-8 levels were seen between TGN/ H. pylori and H. pylori -only cells or between TGN/PMA and PMA-only cells. Finally, TGN-treated AGS cells had increased Muc1 promoter activity, as measured using a Muc1-luciferase reporter gene, and greater MUC1 protein levels by Western blot analysis, compared with vehicle controls. These results support the hypothesis that PPARγ stimulates MUC1 expression by AGS cells, thereby attenuating H. pylori - and PMA-induced IL-8 production.

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The PPAR Gamma Agonist Troglitazone Regulates Erk 1/2 Phosphorylation via a PPARγ-Independent, MEK-Dependent Pathway in Human Prostate Cancer Cells

Cited by 40 publications

References 41 publications

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

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