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

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.

• Authors: Diana Zurlo, Gemma Assante, Salvatore Moricca, Vittorio Colantuoni, Angelo Lupo
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1840 Issue 7 Pg. 2361-72 (Jul 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24735796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Ligands
• Naphthalenes
• PPAR gamma
• Sp1 Transcription Factor
• TCF Transcription Factors
• beta Catenin
• cladosporol

Topics

• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• HT29 Cells
• Humans
• Ligands
• Naphthalenes (metabolism, pharmacology)
• PPAR gamma (metabolism)
• Signal Transduction (drug effects)
• Sp1 Transcription Factor (metabolism)
• TCF Transcription Factors (metabolism)
• beta Catenin (metabolism)