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.