Peroxisome Proliferator-Activated Receptor γ Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) might not be permissive to ligand activation in prostate cancer cells. Association of PPARγ with repressing factors or posttranslational modifications in PPARγ protein could explain the lack of effect of PPARγ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPARγ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPARγ agonists, defining a new class of PPARγ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.

Supplemental material for this article may be found at http://mcb.asm.org/.

Jacques Teyssier, Imâde Ait-Arsa, Michel Brissac, and Michelle Turmo are acknowledged for their excellent technical assistance. Members of the Equipe AVENIR and INSERM U540 are acknowledged for support and discussions.

This work was supported by grants from INSERM (Avenir), CHU de Montpellier, Association pour la Recherche contre le Cancer, Alfediam, Ligue contre le Cancer, and Fondation pour la Recherche Médicale. I.I. was supported by a grant from Ligue Nationale contre le Cancer, D.S. by the Boehringer Ingelheim Fonds Ph.D. scholarship program, and A.A. by a grant of INSERM poste vert.