A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Activation of the Wnt/beta-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based beta-catenin/Tcf - responsive reporter. We identified FH535, a compound that suppresses both Wnt/beta-catenin and peroxisome proliferator - activated receptor (PPAR) signaling. FH535 antagonizes both PPAR gamma and PPAR delta ligand - dependent activation and shows structural similarity to GW9662, a known PPAR gamma antagonist. The effect of FH535 on beta-catenin/Tcf activity is reduced in cells carrying a deletion of the PPAR delta gene, as well as by the PPAR gamma agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the co-activators beta-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of beta-catenin recruitment, in comparison with GW9662, is linked to FH535's unique capability to inhibit the Wnt/beta-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer.