Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS).
Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS).
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DOI：
10.18632/oncotarget.9112
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Lacey A;Hedrick E;Li X;Patel K;Doddapaneni R;Singh M;Safe S
孤儿核受体NR4A1在横纹肌肉瘤（rhabdomyosarcoma， RMS）患者的肿瘤以及Rh30和RD RMS细胞系中表达，我们利用RNA干扰（RNAi）研究了该受体在RMS细胞中的作用。NR4A1在Rh30细胞中表达下调，可抑制细胞增殖，诱导膜联蛋白V染色，诱导聚磷酸核糖聚合酶（PARP）裂解，结果与其他实体瘤相似。既往研究表明，NR4A1通过调控富含gc启动子的促生长/促生存基因的表达，通过抑制p53激活mTOR，并通过调控异柠檬酸脱氢酶1 （IDH1）和硫氧还蛋白结构域5 （TXNDC5）的表达维持低氧化应激。RNAi研究结果表明，NR4A1也调节RMS细胞中的这些通路和相关基因，从而表现出促癌活性。含有对羟基（dim -c - phoh）和对羧甲基（DIM-C-pPhCO2Me）取代基的1,1-双（3-吲哚基）-1-（对取代苯基）甲烷（C-DIM）类似物是NR4A1配体，可降低RMS细胞中NR4A1依赖性的转激活，抑制RMS细胞和肿瘤生长，诱导细胞凋亡。此外，NR4A1敲低和C-DIM/NR4A1拮抗剂的作用与NR4A1依赖基因/途径的抑制剂相当。在突变型p53 RMS细胞中，NR4A1敲除和DIM-C-pPhOH和DIM-C-pPhCO2Me处理均可诱导激活应激基因的ROS和诱导激活AMPK并抑制mTOR的sestrin 2。由于NR4A1调节了RMS中几种促进生长/促生存的途径，C-DIM/NR4A1拮抗剂代表了一种新的基于机制的方法，可以单独或联合治疗RMS，从而减少当前细胞毒性治疗的不良影响。
The orphan nuclear receptor NR4A1 is expressed in tumors from rhabdomyosarcoma (RMS) patients and Rh30 and RD RMS cell lines, and we used RNA interference (RNAi) to investigate the role of this receptor in RMS cells. Knockdown of NR4A1 in Rh30 cells decreased cell proliferation, induced Annexin V staining and induced polyADPribose polymerase (PARP) cleavage and these results were similar to those observed in other solid tumors. Previous studies show that NR4A1 regulates expression of growth promoting/pro-survival genes with GC-rich promoters, activates mTOR through suppression of p53, and maintains low oxidative stress by regulating expression of isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain containing 5 (TXNDC5). Results of RNAi studies demonstrated that NR4A1 also regulates these pathways and associated genes in RMS cells and thereby exhibits pro-oncogenic activity. 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methane (C-DIM) analogs containing p-hydroxyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) substituents are NR4A1 ligands that decreased NR4A1-dependent transactivation in RMS cells and inhibited RMS cell and tumor growth and induced apoptosis. Moreover, the effects of NR4A1 knockdown and the C-DIM/NR4A1 antagonists were comparable as inhibitors of NR4A1-dependent genes/pathways. Both NR4A1 knockdown and treatment with DIM-C-pPhOH and DIM-C-pPhCO2Me also induced ROS which activated stress genes and induced sestrin 2 which activated AMPK and inhibited mTOR in the mutant p53 RMS cells. Since NR4A1 regulates several growth-promoting/pro-survival pathways in RMS, the C-DIM/NR4A1 antagonists represent a novel mechanism-based approach for treating this disease alone or in combination and thereby reducing the adverse effects of current cytotoxic therapies.
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影响因子：
5.6
作者：
Horna-Terrón E;Pradilla-Dieste A;Sánchez-de-Diego C;Osada J
通讯作者：
Osada J
影响因子：
11.2
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
通讯作者：
Safe S
影响因子：
--
作者：
Lee, Syng-Ook;Li, Xi;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
5.3
作者：
Kolluri, SK;Bruey-Sedano, N;Zhang, XK
通讯作者：
Zhang, XK
影响因子：
8
作者：
Lee, S-O;Andey, T.;Jin, U-H;Kim, K.;Sachdeva, M.;Safe, S.
通讯作者：
Safe, S.