MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy
MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy
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DOI：
10.1016/j.ygyno.2019.08.014
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发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Meng, Xiangbing
中科院分区：
文献类型：
--
作者：
Bi, Jianling;Areecheewakul, Sudartip;Meng, Xiangbing
目的：铂类化合物已被广泛用作多种癌症的主要治疗药物。然而，耐药性是转移性或复发性疾病患者治疗失败的主要原因，因此突出了确定导致铂化合物耐药性的新因素的必要性。Metadherin（MTDH，也称为AEG-1和LYRIC）位于8号染色体的一个频繁扩增的区域，一直与化疗药物的耐药性相关，尽管确切的机制仍然不完全defined.Methods：FANCD 2和FANCI的mRNA通过RNA结合蛋白免疫沉淀被拉低。使用纳米沉淀法制备了负载Pristimerin的纳米颗粒。免疫功能低下的小鼠患者来源的异种移植瘤进行了治疗与pristimerin装载的纳米粒子，顺铂和两者的组合。结果：MTDH，通过其最近发现的作用作为RNA结合蛋白，调节FANCD 2和FANCI的表达，两个组成部分的范可尼贫血互补组（FA），发挥关键作用的链间交联损伤诱导铂化合物。Pristimerin是一种来自卫矛科成员的醌甲基化三萜类提取物，用于治疗中医炎症，显著降低癌细胞中的MTDH，FANCD 2和FANCI水平，从而恢复对铂类化疗的敏感性。使用患者来源的子宫内膜癌异种移植模型，我们发现，在一种新的纳米颗粒制剂与pristimerin治疗显着抑制肿瘤生长时，与cisplatin.Conclusions：MTDH参与转录后调控FANCD 2和FANCI。Pristimerin可通过抑制FA途径增加MTDH过表达肿瘤对铂类药物的敏感性。(C)2019年爱荷华州大学。爱思唯尔公司出版
Objective: Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined.Methods: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerin-loaded nanoparticles, cisplatin and a combination of the two.Results: MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinone-methide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin.Conclusions: MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway. (C) 2019 University of Iowa. Published by Elsevier Inc.