The Wnt/β-catenin signaling pathway targets PPARγ activity in colon cancer cells

Jansson, Emmelie Å.; Are, Alexandra; Greicius, Gediminas; Kuo, I‐Chun; Kelly, Denise; Arulampalam, Velmurugesan; Pettersson, Sven

doi:10.1073/pnas.0405928102

Cited by 143 publications

(114 citation statements)

References 42 publications

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“…It also might account for the inefficacity of PPARγ-based therapy, such as 5-aminosalicylates, in the colon of CD patients with colonic involvement compared with UC patients. Whether a maintained DEFB1 expression level might be necessary to account for the protective effect of PPARγ on the development of colorectal cancer will require additional investigation (21,22). In summary, we believe that restoring PPARγ-dependent antimicrobial barrier function might prevent and/or cure inflammatory lesions in the colon of patients with CD.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Peyrin–Biroulet

Beisner

Wang

et al. 2010

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

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178

137

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Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is essential for intestinal homeostasis in response to both dietaryand microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARγ functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of β-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Pparγ mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARγ-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARγ-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.β-defensin 1 | Crohn's disease | microbiota | nutrition | PPAR-γ

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Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Peyrin–Biroulet

Beisner

Wang

et al. 2010

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

Self Cite

178

137

View full text Add to dashboard Cite

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“…The direct binding of androgen receptor to h-catenin and Tcf4 is thought to mediate the regulation of Wnt signaling. Like the androgen receptor, PPARg interacts with h-catenin and is found in a complex with Tcf4 (5,40). Thus, it is conceivable that FH535 inhibits a complex containing PPARg h-catenin and Tcf/Lef proteins, depriving the complex bound to Tcf/Lef DNA sites from trans-activating.…”

Section: Discussionmentioning

confidence: 99%

“…On the transcriptional level, h-catenin enhances PPARg activity whereas PPARy is a target for h-catenin/Tcf regulation (5,6). A clear interaction between these pathways is observed during adipogenesis.…”

Section: Introductionmentioning

confidence: 95%

“…FH535 Inhibits B-Catenin and GRIP1 Recruitment to PPAR; and PPARD To investigate the mechanism in which FH535 suppresses h-catenin/Tcf and PPAR-dependent transactivation, we focused on h-catenin and the coactivator GRIP1 because (5,31,32). PPARs recruitment of these factors and the corepressors NCoR and SMRT was studied using a mammalian two-hybrid assay, in which activation of a gal4-dependent reporter is regulated by the interaction between VP16-PPARs with the gal4-transcription factor chimera.…”

Section: Both Serum and Lysophosphatidic Acid Reduce Fh535 Inhibitionmentioning

confidence: 99%

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

Handeli

Simon

2008

Molecular Cancer Therapeutics

165

143

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Activation of the Wnt/B-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based B-catenin/Tcf -responsive reporter. We identified FH535, a compound that suppresses both Wnt/B-catenin and peroxisome proliferator -activated receptor (PPAR) signaling. FH535 antagonizes both PPAR; and PPARD ligand -dependent activation and shows structural similarity to GW9662, a known PPAR; antagonist. The effect of FH535 on B-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARd gene, as well as by the PPAR; agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators B-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of B-catenin recruitment, in comparison with GW9662, is linked to FH535 ¶s unique capability to inhibit the Wnt/B-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521 -9]

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“…Namely, activation of PPARg with two different synthetic agonists increased the number and size of colon tumors in Apc Min mice (Lefebvre et al, 1998). Interestingly, Wnt/b-catenin signaling targets PPARg in colon cancer cells (Jansson et al, 2005). However, it has been excluded from the direct targets of the Wnt signal.…”

Section: Modifier Genes Of Apc Intestinal Polyposismentioning

confidence: 99%

Wnt signaling and gastrointestinal tumorigenesis in mouse models

Taketo

2006

Oncogene

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The canonical Wnt signaling plays important roles in embryonic development and tumorigenesis. For the latter, induced mutations in mice have greatly contributed to our understanding of the molecular mechanisms of cancer initiation and progression. Here, I will review recent reports on gastrointestinal cancer model mice, with an emphasis on the roles of the Wnt signal pathway. They include: mouse models for familial adenomatous polyposis; modifying factors that affect mouse intestinal polyposis, including the genes that help cancer progression; Wnt target genes that affect mouse intestinal polyposis; and a mouse model of gastric cancer that mimics Helicobacter pyroli infection.

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The Wnt/β-catenin signaling pathway targets PPARγ activity in colon cancer cells

Abstract: Control of colon cell fate in adenocarcinomas is

Cited by 143 publications

References 42 publications

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

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

Wnt signaling and gastrointestinal tumorigenesis in mouse models

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