核受体 4A1（NR4A1）拮抗剂诱导子宫内膜癌细胞中 ROS 依赖的 mTOR 信号抑制。
Nuclear receptor 4A1 (NR4A1) antagonists induce ROS-dependent inhibition of mTOR signaling in endometrial cancer.
机构信息
Department of Veterinary Physiology and Pharmacology, Texas AM University, College Station, TX 77843, USA.
Department of Medical Physiology, College of Medicine, Texas AM University, College Station, TX 77843, USA.
出版信息
Gynecol Oncol. 2019 Jul;154(1):218-227. doi: 10.1016/j.ygyno.2019.04.678. Epub 2019 Apr 30.
OBJECTIVES
NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR.
METHODS
Ishikawa and Hec-1B endometrial cells were used as models to investigate the parallel effects of NR4A1 knockdown by RNA interference (siNR4A1) and treatment with bis-indole-derived NR4A1 ligands (antagonists) on cell growth and survival by determining cell numbers and effects on Annexin V staining. Western blot analysis of whole cell lysates was used to determine effects of these treatments on expression of growth promoting, survival and apoptotic genes and mTOR signaling. Effects of NR4A1 antagonists on tumor growth were determined in athymic nude mice bearing Hec-1B cells as xenografts.
RESULTS
siNR4A1 or treatment with bis-indole-derived NR4A1 antagonists inhibited growth of endometrial cancer cells in vitro and endometrial tumors in vivo and this was accompanied by decreased expression of growth promoting and survival genes and mTOR inhibition.
CONCLUSIONS
NR4A1 exhibited pro-oncogenic activity in endometrial cells due, in part, to regulation of cell growth, survival and mTOR signaling, and all of these pathways and their associated gene products were inhibited after treatment with bis-indole-derived NR4A1 antagonists. Moreover, these compounds also blocked endometrial tumor growth in vivo demonstrating that NR4A1 is a potential novel drug target for treatment of endometrial cancer.
目的
NR4A1 在许多实体瘤中过表达，本研究旨在探讨该受体在子宫内膜癌细胞中的表达和功能作用，并证明 NR4A1 拮抗剂抑制 mTOR。
方法
以 Ishikawa 和 Hec-1B 子宫内膜细胞为模型，通过 RNA 干扰（siNR4A1）和用双吲哚衍生的 NR4A1 配体（拮抗剂）处理来研究 NR4A1 敲低的平行作用，通过确定细胞数量和对 Annexin V 染色的影响来研究细胞生长和存活。使用全细胞裂解物的 Western blot 分析来确定这些处理对促进生长、存活和凋亡基因和 mTOR 信号的表达的影响。用 NR4A1 拮抗剂处理荷有 Hec-1B 细胞的裸鼠，以确定其对肿瘤生长的影响。
结果
siNR4A1 或用双吲哚衍生的 NR4A1 拮抗剂处理可抑制子宫内膜癌细胞在体外和体内的生长，这伴随着促进生长和存活基因的表达减少以及 mTOR 抑制。
结论
NR4A1 在子宫内膜细胞中表现出致癌活性，部分原因是调节细胞生长、存活和 mTOR 信号，所有这些途径及其相关基因产物在用双吲哚衍生的 NR4A1 拮抗剂处理后都被抑制。此外，这些化合物还能阻断体内子宫内膜肿瘤的生长，表明 NR4A1 是治疗子宫内膜癌的一个潜在的新型药物靶点。
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