PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer
PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer
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DOI：
10.1530/erc-12-0240
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发表时间：
2013-06-01
影响因子：
3.9
通讯作者：
Festuccia, Claudio
中科院分区：
文献类型：
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作者：
Gravina, Giovanni Luca;Marampon, Francesco;Festuccia, Claudio
雄激素去势治疗期间雄激素受体(AR)的异常激活或“重新激活”可能是抗去势前列腺癌发生的一个潜在原因。这项研究测试了PXD101，一种有效的组蛋白脱乙酰酶(HDAC)抑制剂，可以防止去势抵抗表型的发生，并加强激素治疗。一组具有分级的去势抵抗表型的人前列腺癌细胞和体内模型被用来验证这一假设。在这份报告中，我们证明激素调控有利于抗去势表型的开始，增加HDAC的表达和活性，并调节AR、EGFR、HER2和Akt的表达和活性。与这些观察一致的是，PXD101对HDACs的功能性敲除通过显著下调AR、EGFR、HER2和Akt的表达/活性来阻止去势抵抗表型的发生。HDAC6与HSP90之间以及GSK-3β与CRM1之间功能协同的失调可能解释了PXD101的生物学效应。在这一点上，HDAC6沉默或17AAG对HSP90的功能性敲除导致AR、EGFR、HER2和Akt表达/活性的选择性下调，而PXD101介导的GSK-3b磷酸化减少增加了CRM1的核表达，进而改变了AR和Survivin的循环，增加了caspase3的活性。HDAC抑制剂保留了阻止去势抵抗表型发病的能力，因此，值得在这种情况下进行临床研究。然而，需要更多的数据来制定这一疾病阶段的临床治疗策略。
Aberrant activation or 'reactivation' of androgen receptor (AR) during androgen ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that PXD101, a potent pan histone deacetylase (HDAC) inhibitor, may prevent onset of castration-resistant phenotype and potentiate hormonal therapy. A panel of human prostate cancer cells with graded castration-resistant phenotype and in vivo models were used to verify this hypothesis. In this report, we demonstrated that hormonal manipulation favors the onset of castration-resistant phenotype increasing HDAC expression and activity as well as modulating expression and activity of AR, EGFR, HER2, and Akt. Consistent with these observations, the functional knockdown of HDACs by PXD101 prevented the onset of castration-resistant phenotype with a significant downregulation of AR, EGFR, HER2, and Akt expression/activity. The dysregulation of functional cooperation between HDAC6 with hsp90, on the one hand, and between GSK-3 beta with CRM1, on the other hand, may explain the biological effects of PXD101. In this regard, the HDAC6 silencing or the functional knockdown of hsp90 by 17AAG resulted in the selective downregulation of AR, EGFR, HER2, and Akt expression/activity, while the decreased phosphorylation of GSK-3b mediated by PXD101 increased the nuclear expression of CRM1, which in turn modified the AR and survivin recycling with increased caspase 3 activity. HDAC inhibitors retain the ability to prevent the onset of castration-resistant phenotype and, therefore, merit clinical investigation in this setting. However, additional data are needed to develop clinical treatment strategies for this disease stage.