Murine Double Minute 2 siRNA and wild-type p53 gene therapy interact positively with zinc on prostate tumours in vitro and in vivo
Murine Double Minute 2 siRNA and wild-type p53 gene therapy interact positively with zinc on prostate tumours in vitro and in vivo
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DOI：
10.1016/j.ejca.2013.12.027
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发表时间：
2014-04-01
影响因子：
8.4
通讯作者：
Cai, Lu
中科院分区：
文献类型：
--
作者：
Gu, Junlian;Wang, Bo;Cai, Lu
前列腺癌（PCa）通常表现为p53基因突变或P53蛋白失活。后者可能是由于小鼠双微体2同源物（MDM 2）的上调，MDM 2既作为E3泛素连接酶通过蛋白酶体降解P53蛋白，又作为P53转录激活的抑制剂。锌在稳定P53 DNA结合结构域中起着至关重要的作用，但PCa细胞通常缺乏积累足够锌的能力。在本研究中，我们探讨了最佳的方法来保留P53功能。为了恢复PCa中有缺陷的P53通路，我们探索了Pmp 53 [一种含有mdm 2小干扰RNA（Si-MDM 2）和野生型p53基因的质粒]与锌的联合治疗。这种治疗保留了野生型P53的构象和功能，在体外和体内的前列腺癌。联合治疗显着抑制肿瘤异种移植物的生长，保留野生型P53构象，并增强其p21和bax基因表达的转录调控，导致增殖减少和凋亡增加。这些体内发现通过体外培养PCa PC-3（p53无效）或DU 145（突变型p53）细胞得到证实，并显示了联合治疗对细胞周期阻滞和大量凋亡的积极作用。我们的研究结果表明，Pmp 53与锌的联合治疗是一种有效的策略，可能为某些表达低水平锌和缺陷P53状态的癌症开辟新的治疗途径。(C)2014爱思唯尔有限公司版权所有。
Prostate cancer (PCa) often shows either mutations of the p53 gene or inactivation of the P53 protein. The latter may be due to up-regulation of mouse double minute 2 homologue (MDM2), which functions both as an E3 ubiquitin ligase to degrade P53 protein via the proteasome and an inhibitor of P53 transcriptional activation. Zinc plays a crucial role in stabilizing the P53 DNA binding domain, but PCa cells often lack the ability to accumulate sufficient zinc. In the present study, we explore the optimal approach to retention of P53 function. To restore the defective P53 pathway in PCa, we have explored a combined treatment of Pmp53 [a plasmid containing both mdm2 small interfering RNA (Si-MDM2) and the wild-type p53 gene] with zinc. This treatment retains the wild-type P53 conformation and function in PCa in vitro and in vivo. Combined treatments significantly inhibited tumour xenograft growth, retaining wild-type P53 conformation and enhancing its transcriptional regulation of p21 and bax gene expression, leading to the decreased proliferation and increased apoptosis. These in vivo findings were confirmed by in vitro culture of PCa PC-3 (p53 null) or DU145 (mutant p53) cells and showed a positive effect of the combined therapy on cell cycle arrest and massive apoptosis. Our findings suggest that the combined therapy of Pmp53 with zinc is an effective strategy that may open a new therapeutic avenue in some cancers expressing low levels of zinc and a defective P53 status. (C) 2014 Elsevier Ltd. All rights reserved.