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Biochim Biophys Acta. 2014 Jul;1840(7):2361-72. doi: 10.1016/j.bbagen.2014.04.007. Epub 2014 Apr 13.

Cladosporol A, a new peroxisome proliferator-activated receptor γ (PPARγ) ligand, inhibits colorectal cancer cells proliferation through β-catenin/TCF pathway inactivation.

Author information

1
Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
2
Dipartimento di Patologia Vegetale, Università degli Studi di Milano, via Celoria, 2, 20133 Milano, Italy.
3
Dipartimento di Scienze delle Produzioni Agroalimentari e dell'Ambiente (DiSPAA), Università degli Studi di Firenze, Piazzale delle Cascine, 2850144 Firenze, Italy.
4
Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100 Benevento, Italy. Electronic address: lupo@unisannio.it.

Abstract

BACKGROUND:

Cladosporol A, a secondary metabolite from Cladosporium tenuissimum, exhibits antiproliferative properties in human colorectal cancer cells by modulating the expression of some cell cycle genes (p21(waf1/cip1), cyclin D1).

METHODS:

PPARγ activation by cladosporol A was studied by overexpression and RNA interference assays. The interactions between PPARγ and Sp1 were investigated by co-immunoprecipitation and ChIp assays. β-Catenin subcellular distribution and β-catenin/TCF pathway inactivation were analyzed by western blot and RTqPCR, respectively. Cladosporol A-induced β-catenin proteasomal degradation was examined in the presence of the specific inhibitor MG132.

RESULTS:

Cladosporol A inhibits cell growth through upregulation of p21(waf1/cip1) gene expression mediated by Sp1-PPARγ interaction. Exposure of HT-29 cells to cladosporol A causes β-catenin nuclear export, proteasome degradation and reduced expression of its target genes. Upon treatment, PPARγ also activates E-cadherin gene at the mRNA and protein levels.

CONCLUSION:

In this work we provide evidence that PPARγ mediates the anti-proliferative action of cladosporol A in colorectal cancer cells. Upon ligand activation, PPARγ interacts with Sp1 and stimulates p21(waf1/cip1) gene transcription. PPARγ activation causes degradation of β-catenin and inactivation of the downstream target pathway and, in addition, upregulates E-cadherin expression reinforcing cell-cell interactions and a differentiated phenotype.

GENERAL SIGNIFICANCE:

We elucidated the molecular mechanisms by which PPARγ mediates the anticancer activity of cladosporol A.

KEYWORDS:

Cell proliferation; Cladosporol A; E-cadherin; Transcription; p21(waf1/cip1); β-catenin

PMID:
24735796
DOI:
10.1016/j.bbagen.2014.04.007
[Indexed for MEDLINE]
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