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 (p21waf1/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 p21waf1/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 p21waf1/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.
|Titolo:||Cladosporol A, a new Peroxisome Proliferator-Activated Receptor γ (PPARγ) ligand, inhibits colorectal cancer cells proliferation through β-catenin/TCF pathway inactivation|
|Data di pubblicazione:||2014|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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