Repression of beta-catenin signaling by PPAR gamma ligands.

Aberrant activation of the Wnt/beta-catenin signaling pathway plays a crucial role in oncogenesis of various human malignancies. It has been demonstrated that there is a direct interaction between beta-catenin and PPAR gamma. Here we examined the effects of fifteen reported PPAR ligands in a reporter gene assay that is dependent on beta-catenin activation of TCF/LEF transcription factors; only the thiazolidinedione PPAR gamma agonists troglitazone, rosiglitazone and pioglitazone, and a non-thiazolidinedione PPAR gamma activator GW1929 inhibited beta-catenin-induced transcription in a PPAR gamma dependent fashion. The results from mammalian one-hybrid experiments showed that functional PPAR gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. However, a PPAR gamma activator Fmoc-Leu could not repress beta-catenin-mediated signaling and its transactivation activity. These results indicate that activation of PPAR gamma is necessary, but not sufficient, for the beta-catenin antagonistic activity of a PPAR gamma agonist, and that the inhibitory compounds interfere directly with beta-catenin transactivation activity. (c) 2010 Elsevier B.V. All rights reserved.