Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells.
Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells.
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DOI：
10.18632/oncotarget.23569
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发表时间：
2018-01-19
期刊：
影响因子：
--
通讯作者：
Zhu, Yan
中科院分区：
文献类型：
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作者：
Chopra, Harman;Khan, Zara;Zhu, Yan
去势抵抗前列腺癌(CRPC)在最初的标准放疗和雄激素剥夺治疗后经常发生，给患者留下了有限的进一步治疗选择。雄激素受体(AR)是一种转录因子，在前列腺癌的发生发展中起关键作用。P53是一种主要的肿瘤抑制基因，在前列腺癌的早期阶段很少发生突变，在前列腺癌进展过程中经常被解除调控。在这里，我们报告了一个不寻常的共同扩增MDM2和MDMX，两个关键的负调控的p53，在CRPC数据集中。我们证明，MDM2和MDMX分别与Nutlin-3和NSC207895联合抑制，对携带雄激素反应性野生型TP53基因的前列腺癌LNCaP和22Rv1细胞的增殖有深刻的抑制作用。我们进一步表明，MDM2和MDMX的联合抑制不仅激活了P53，而且降低了细胞内AR的水平，抑制了它的功能。此外，MDM2和MDMX的共同表达可以稳定AR。总之，我们的结果表明，联合抑制MDM2和MDMX可能为前列腺癌治疗提供一种新的引人注目的策略。
Castration-resistant prostate cancer (CRPC) frequently develops after initial standard radiation and androgen deprivation therapy, leaving patients with limited further treatment options. Androgen receptor (AR) is a transcription factor that plays a key role in the initiation and progression of prostate cancer. p53, a major tumor suppressor that is rarely mutated in early-stages of prostate cancer, is often deregulated during prostate cancer progression. Here, we report an unusual co-amplification of MDM2 and MDMX, two crucial negative regulators of p53, in CRPC datasets. We demonstrate that combinatorial inhibition of MDM2 and MDMX, with nutlin-3 and NSC207895 respectively, has a profound inhibitory effect on cell proliferation of androgen-responsive, wild-type TP53 gene carrying prostate cancer cells LNCaP and 22Rv1. We further show that the combinatorial inhibition of MDM2 and MDMX not only activates p53, but also decreases cellular levels of AR and represses its function. Additionally, co-expression of MDM2 and MDMX stabilizes AR. Together, our results indicate that combinatorial inhibition of MDM2 and MDMX may offer a novel compelling strategy for prostate cancer therapy.