Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma.
Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma.
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DOI：
10.1371/journal.pone.0128308
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Abudayyeh A
中科院分区：
文献类型：
--
作者：
Hedrick E;Lee SO;Kim G;Abdelrahim M;Jin UH;Safe S;Abudayyeh A
孤儿核受体NR4A1在癌细胞系中表现出促癌活性。NR4A1激活mTOR信号，调控硫氧还蛋白结构域5和异柠檬酸脱氢酶1等维持低氧化应激的基因，并协同激活特异性蛋白1 （Sp1）调控的促生存和促生长基因。用靶向NR4A1的寡核苷酸转染肾细胞癌（RCC） ACHN和786-O细胞可导致细胞增殖减少40-60%，并诱导凋亡。NR4A1在RCC细胞中表达下调bcl-2、survivin和表皮生长因子受体表达，抑制mTOR信号，诱导氧化应激和内质网应激，降低TXNDC5和IDH1。我们最近证明了选择的1,1-二（3'-吲哚基）-1-（对取代苯基）甲烷（C-DIM）化合物，包括对羟基苯基（dim -c - phoh）和对羧甲基（DIM-C-pPhCO2Me）类似物结合NR4A1并作为拮抗剂。dim - c - phoh和DIM-C-pPhCO2Me均能抑制ACHN和786-O细胞的生长并诱导凋亡，NR4A1拮抗剂的功能和基因组效应与NR4A1敲除后的效果相当。这些结果表明，NR4A1拮抗剂靶向RCC细胞和肿瘤（异种移植物）中促进生长和促生存的多种途径，代表了一种治疗RCC的新化疗方法。
The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40–60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p-hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC.
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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：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
11
作者：
Dorđević G;Matušan Ilijaš K;Hadžisejdić I;Maričić A;Grahovac B;Jonjić N
通讯作者：
Jonjić N