Phenylarsine Oxide Can Induce the Arsenite-Resistance Mutant PML Protein Solubility Changes.
Phenylarsine Oxide Can Induce the Arsenite-Resistance Mutant PML Protein Solubility Changes.
复制标题
氧化苯胂可诱导亚砷酸盐抗性突变体 PML 蛋白溶解度变化
DOI：
10.3390/ijms18020247
复制
发表时间：
2017-01-25
影响因子：
5.6
通讯作者：
Naranmandura H
中科院分区：
文献类型：
--
作者：
Jiang YH;Chen YJ;Wang C;Lan YF;Yang C;Wang QQ;Hussain L;Maimaitiying Y;Islam K;Naranmandura H
三氧化二砷（As_2O_3）是近年来治疗急性早幼粒细胞白血病（APL）最有效的药物之一，其分子机制也得到了广泛的研究。然而，已有研究表明，早幼粒细胞白血病（promyelocytic leukemia，PML）基因B-box 2型基序的点突变导致As 2 O3耐药。在本研究中，我们首次建立了有机砷物种氧化苯胂（PAO）是否可以诱导突变PML-IV（A216 V）蛋白质溶解度的变化和降解。这里，三种不同的PML蛋白变体（即，PML-IV、PML-V和突变PML-A216 V）在HEK 293 T细胞中过表达，然后以时间和剂量依赖性方式暴露于PAO。有趣的是，发现PAO对诱导突变PML-IV（A216 V）蛋白溶解度变化和降解具有潜在作用，但在暴露于高浓度的iAsIII、二甲基亚胂酸（DMAIII）和阿霉素（阿霉素）后没有发现明显的作用，即使它们引起细胞死亡。我们目前的数据有力地表明，PAO对突变型PML蛋白溶解度的变化有良好的影响，这可能有助于改善砷耐药APL治疗策略的近期发展。
Arsenic trioxide (As2O3) has recently become one of the most effective drugs for treatment of patient with acute promyelocytic leukemia (APL), and its molecular mechanism has also been largely investigated. However, it has been reported that As2O3 resistant patients are frequently found in relapsed APL after consolidation therapy, which is due to the point mutations in B-box type 2 motifs of promyelocytic leukemia (PML) gene. In the present study, we for the first time establish whether organic arsenic species phenylarsine oxide (PAO) could induce the mutant PML-IV (A216V) protein solubility changes and degradation. Here, three different PML protein variants (i.e., PML-IV, PML-V and mutant PML-A216V) were overexpressed in HEK293T cells and then exposed to PAO in time- and dose-dependent manners. Interestingly, PAO is found to have potential effect on induction of mutant PML-IV (A216V) protein solubility changes and degradation, but no appreciable effects were found following exposure to high concentrations of iAsIII, dimethylarsinous acid (DMAIII) and adriamycin (doxorubicin), even though they cause cell death. Our current data strongly indicate that PAO has good effects on the mutant PML protein solubility changes, and it may be helpful for improving the therapeutic strategies for arsenic-resistant APL treatments in the near future.