Annicotte Jean-Sébastien, Iankova Irena, Miard Stéphanie, Fritz Vanessa, Sarruf David, Abella Anna, Berthe Marie-Laurence, Noël Danièle, Pillon Arnaud, Iborra François, Dubus Pierre, Maudelonde Thierry, Culine Stéphane, Fajas Lluis
Equipe Avenir, INSERM U540, 60 rue de Navacelles, F-34090 Montpellier, France.
Mol Cell Biol. 2006 Oct;26(20):7561-74. doi: 10.1128/MCB.00605-06.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）在前列腺癌细胞中可能不允许配体激活。PPARγ与抑制因子的关联或PPARγ蛋白的翻译后修饰可以解释在最近一项随机临床试验中PPARγ配体缺乏效果的原因。在本研究中，我们使用细胞和前列腺癌异种移植小鼠模型证明，与单独使用每种疗法相比，联合使用PPARγ激动剂吡格列酮和组蛋白去乙酰化酶抑制剂丙戊酸进行治疗在抑制前列腺肿瘤生长方面更有效。我们表明联合治疗损害了小鼠前列腺癌细胞的骨侵袭潜能。此外，我们证明，参与细胞迁移和侵袭控制的蛋白质E-钙黏蛋白的表达在丙戊酸和吡格列酮存在时高度上调。我们表明E-钙黏蛋白表达仅对联合治疗有反应，而对单一PPARγ激动剂无反应，从而定义了一类新的PPARγ靶基因。这些结果为前列腺癌的治疗开辟了新的治疗前景。
