Peroxisome proliferator-activated receptor gamma (PPARgamma) might not be permissive to ligand activation in prostate cancer cells. Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma 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 PPARgamma 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 PPARgamma agonists, defining a new class of PPARgamma target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.
Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer
Annicotte, J. S.; Iankova, I.; Miard, S.; Fritz, V.; Sarruf, D.; Abella, A.; Berthe, M. L.; Noel, D.; Pillon, A.; Iborra, F.; Dubus, P.; Maudelonde, T.; Culine, S.; Fajas, L.
Mol Cell Biol
2006-10 / vol 26 / pages 7561-74
26/20/7561 [pii] 10.1128/MCB.00605-06
0270-7306 (Print) 0270-7306 (Linking)
Cell Line, Tumor; Humans; Animals; Mice; Male; Disease Models, Animal; RNA, Messenger/genetics; Cell Proliferation/drug effects; Enzyme Inhibitors/pharmacology; Histone Deacetylases/metabolism; Gene Expression Regulation, Neoplastic; Phosphorylation/drug effects; Cadherins/genetics/*metabolism; Disease Progression; Drug Therapy, Combination; Histone Deacetylase Inhibitors; Neoplasm Invasiveness/pathology; Neoplasm Transplantation; PPAR gamma/agonists/genetics/*metabolism; Prostatic Neoplasms/drug therapy/genetics/*metabolism/*pathology; Retinoblastoma Protein/metabolism; Thiazolidinediones/therapeutic use; Valproic Acid/therapeutic use