A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Handeli, Shlomo; Simon, Julian A.

doi:10.1158/1535-7163.mct-07-2063

Cited by 168 publications

(153 citation statements)

References 45 publications

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“…PPARδ, a widely expressed transcriptional factor, was reported to be a downstream target of WNT/β-catenin signaling. 15,16 He et al 16 found that transfected CRC cells with a dnTCF-4 expression vector significantly suppressed the activity of PPARδ promoter, which suggested that PPARδ was regulated by β-catenin/TCF pathway. We found that activation of WNT/β-catenin signaling by SB216763 reversed the reduction in the PPARδ protein induced by CSE stimulation, which suggested PPARδ may be a downstream target of β-catenin signaling (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

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WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

“…15,16 PPARs are nuclear receptor/ligand-activated transcription factors, composed of three known isoforms: PPARα, PPARδ, and PPARγ. 17 PPARs regulate various cellular processes involving lipid metabolism, glucose homeostasis, and inflammation.…”

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confidence: 99%

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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“…If Wnt/-catenin activity is required for proliferation during this period, then inhibition or activation of the pathway prior to terminal mitosis should result in a reduction or enhancement in the number of proliferating cells, respectively. To test this hypothesis, we utilized an in vitro strategy in which cochlear explants were established at E12 and maintained in one of two different Wnt/-catenin inhibitors: FH535, a specific TCF inhibitor (Handeli and Simon, 2008), or IWR-1, which acts by stabilizing axin and subsequently increasing -catenin degradation . Conversely, some explants were maintained in LiCl, an agonist of Wnt/-catenin signaling that blocks the kinase activity of Gsk3, preventing -catenin degradation (Klein and Melton, 1996).…”

Section: Research Articlementioning

confidence: 99%

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

et al. 2012

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The canonical Wnt/β-catenin signaling pathway is known to play crucial roles in organogenesis by regulating both proliferation and differentiation. In the inner ear, this pathway has been shown to regulate the size of the otic placode from which the cochlea will arise; however, direct activity of canonical Wnt signaling as well as its function during cochlear mechanosensory hair cell development had yet to be identified. Using TCF/Lef:H2B-GFP reporter mice and transfection of an independent TCF/Lef reporter construct, we describe the pattern of canonical Wnt activity in the developing mouse cochlea. We show that prior to terminal mitosis, canonical Wnt activity is high in early prosensory cells from which hair cells and support cells will differentiate, and activity becomes reduced as development progresses. Using an in vitro model we demonstrate that Wnt/β-catenin signaling regulates both proliferation and hair cell differentiation within the developing cochlear duct. Inhibition of Wnt/β-catenin signaling blocks proliferation during early mitotic phases of development and inhibits hair cell formation in the differentiating organ of Corti. Conversely, activation increases the number of hair cells that differentiate and induces proliferation in prosensory cells, causing an expansion of the Sox2-positive prosensory domain. We further demonstrate that the induced proliferation of Sox2-positive cells may be mediated by the cell cycle regulator cyclin D1. Lastly, we provide evidence that the mitotic Sox2-positive cells are competent to differentiate into hair cells. Combined, our data suggest that Wnt/β-catenin signaling has a dual function in cochlear development, regulating both proliferation and hair cell differentiation.

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“…In addition, we indicate that Tcf-4 expression increases significantly with the ascending pathologic grade of gliomas and correlates positively with AKT1 expression. Since specific agents inhibiting β-catenin/Tcf-4 and AKT1 are available (26,27), our data provide the rationale for combining these inhibitors in treating specific forms of cancer, such as in a subset of glioma in which both β-catenin/Tcf-4 and AKT1 are activated.…”

Section: Discussionmentioning

confidence: 93%

β-catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma

Chen

Huang²,

Han³

et al. 2011

Int J Oncol

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Abstract. Increasing evidence suggests that interplays between Wnt/β-catenin and PI3K/AKT signaling cascades are involved in tumor development and progression. However, the exact mechanism in glioma is not well known. Using aspirin, we found that the expression levels of AKT1 in glioma cells significantly correlated with the transcriptional activity of β-catenin. Similar observations were made when we subjected glioma cells to treatment with Tcf4 siRNA. Moreover, both aspirin and Tcf4 siRNA can suppress the proliferation and induce apoptosis of glioma. In addition, our analysis of the gene promoter of AKT1 revealed multiple putative Tcf-4 binding sites. In support of the concept that β-catenin/Tcf-4 is a transcriptional regulator for AKT1, results from our chromatin immunoprecipitation studies and luciferase assay showed that β-catenin/Tcf-4 binds to the potential binding sites in the gene promoter of AKT1. Furthermore, using immunohistochemistry, we found that Tcf-4 protein expression increased significantly in high-grade glioma in comparison to low-grade glioma and correlated with AKT1 expression. In conclusion, our results support the concept that β-catenin/Tcf-4 directly regulates AKT1 in glioma, and these two proteins may cooperate with each other in exerting their oncogenic effects in glioma.

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A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Cited by 168 publications

References 45 publications

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

β-catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma

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