Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy
Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy
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DOI：
10.1530/erc-15-0063
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发表时间：
2015-10-01
影响因子：
3.9
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Hedrick, Erik;Lee, Syng-Ook;Safe, Stephen
孤儿核受体4A 1（NR 4A 1）在乳腺肿瘤和乳腺癌细胞系中过表达。通过用靶向NR 4A 1（siNR 4A 1）的寡核苷酸进行RNA干扰和用NR 4A 1拮抗剂处理来研究该受体的功能活性。用NR 4A 1拮抗剂处理乳腺癌细胞或用siNR 4A转染乳腺癌细胞。在MCF-7、SKBR 3和MDA-MB-231细胞以及携带MDA-MB-231细胞作为异种移植物的无胸腺裸鼠中研究了对细胞增殖和凋亡以及与这些反应相关的特定基因的影响。用siNR 4A 1转染MCF-7、MD-AMB-231和SKBR 3乳腺癌细胞可降低这些细胞系的细胞增殖并诱导凋亡。siNR 4A 1转染乳腺癌细胞还降低了SP调节基因（包括生存素、bcl-2和表皮生长因子受体）的表达，抑制了表达WT p53的MCF-7细胞中的mTOR信号传导，并通过下调含硫氧还蛋白结构域5和异柠檬酸脱氢酶1激活氧化和内质网应激。1，1-双（3 '吲哚基）-1-（p-取代苯基）甲烷（C-DIM）是作为NR 4A 1拮抗剂的NR 4A 1配体。用选定的类似物治疗也抑制乳腺癌细胞和肿瘤生长并诱导细胞凋亡。C-DIM/NR 4A 1拮抗剂的作用与NR 4A 1敲低后观察到的作用相当。siNR 4A 1或C-DIM/NR 4A 1拮抗剂在乳腺癌细胞和肿瘤中的结果与先前在胰腺癌、肺癌和结肠癌细胞中报道的结果相似。他们证明了NR 4A 1拮抗剂在过表达该受体的肿瘤患者中的潜在临床应用。
The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MD-AMB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3'indolyl)-1-(p-substituted phenyl) methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.