Chopra Harman, Khan Zara, Contreras Jamie, Wang Herui, Sedrak Abanob, Zhu Yan
Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
Oncotarget. 2017 Dec 15;9(5):6270-6281. doi: 10.18632/oncotarget.23569. eCollection 2018 Jan 19.
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.
去势抵抗性前列腺癌（CRPC）常在初始标准放疗和雄激素剥夺治疗后出现，使患者进一步的治疗选择有限。雄激素受体（AR）是一种转录因子，在前列腺癌的发生和发展中起关键作用。p53是一种主要的肿瘤抑制因子，在前列腺癌早期很少发生突变，但在前列腺癌进展过程中常失调。在此，我们报告在CRPC数据集中，p53的两个关键负调控因子MDM2和MDMX出现异常共扩增。我们证明，分别用nutlin-3和NSC207895对MDM2和MDMX进行联合抑制，对雄激素反应性、携带野生型TP53基因的前列腺癌细胞LNCaP和22Rv1的细胞增殖有显著抑制作用。我们进一步表明，对MDM2和MDMX的联合抑制不仅激活p53，还降低AR的细胞水平并抑制其功能。此外，MDM2和MDMX的共表达使AR稳定。总之，我们的结果表明，对MDM2和MDMX的联合抑制可能为前列腺癌治疗提供一种新的极具吸引力的策略。
