Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer.
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.
Annicotte
Jean-Sébastien
JS
Equipe Avenir, INSERM U540, 60 rue de Navacelles, F-34090 Montpellier, France.
Iankova
Irena
I
Miard
Stéphanie
S
Fritz
Vanessa
V
Sarruf
David
D
Abella
Anna
A
Berthe
Marie-Laurence
ML
Noël
Danièle
D
Pillon
Arnaud
A
Iborra
François
F
Dubus
Pierre
P
Maudelonde
Thierry
T
Culine
Stéphane
S
Fajas
Lluis
L
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use; D014635:Valproic Acid / Q000627:therapeutic use
D015820:Cadherins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D045162:Thiazolidinediones; D014635:Valproic Acid; D006655:Histone Deacetylases; D000077205:Pioglitazone