This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Handeli, S. Articles by Simon, J. A. PubMed PubMed Citation Articles by Handeli, S. Articles by Simon, J. A.

Research Articles: Therapeutics, Targets, and Development

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

Clinical Research and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Julian A. Simon, Fred Hutchinson Cancer Research Center, D2-100, 1100 Fairview Avenue North, Seattle, WA 98109. Phone: 206-667-6241; Fax: 206-667-5255. E-mail: jsimon{at}fhcrc.org

Abstract

Activation of the Wnt/β-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 β-catenin/Tcf–responsive reporter. We identified FH535, a compound that suppresses both Wnt/β-catenin and peroxisome proliferator–activated receptor (PPAR) signaling. FH535 antagonizes both PPAR and PPAR ligand–dependent activation and shows structural similarity to GW9662, a known PPAR antagonist. The effect of FH535 on β-catenin/Tcf activity is reduced in cells carrying a deletion of the PPAR gene, as well as by the PPAR agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators β-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of β-catenin recruitment, in comparison with GW9662, is linked to FH535's unique capability to inhibit the Wnt/β-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. [Mol Cancer Ther 2008;7(3):521–9]

Grant support: Clinical Research Division, Fred Hutchinson Cancer Research Center (J.A. Simon).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/12/07; revised 10/31/07; accepted 12/11/07.