The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells.
The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells.
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DOI：
10.1158/1541-7786.mcr-13-0567
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发表时间：
2014-04
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影响因子：
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通讯作者：
Safe S
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文献类型：
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作者：
Lee SO;Jin UH;Kang JH;Kim SB;Guthrie AS;Sreevalsan S;Lee JS;Safe S
NR 4A 1（Nur 77，TR 3）是一种孤儿核受体，在胰腺癌中过表达，并表现出促癌活性。RNAi干扰Panc-1细胞中NR 4A 1的表达诱导了细胞凋亡，随后的蛋白质组学分析揭示了内质网（ER）应激的几种标志物的诱导，包括葡萄糖相关蛋白78（GRP 78），CCAAT/增强子结合蛋白同源蛋白（CHOP）和转录激活因子-4（ATF-4）。用NR 4A 1拮抗剂1，1-二（3′-吲哚基）-1-（对羟基苯基）甲烷（DIM-C-pPhOH）处理胰腺癌细胞，得到类似的结果。此外，NR 4A 1敲除和DIM-C-pPhOH均诱导活性氧（ROS），并且在与抗氧化剂共处理后，这些试剂对ROS和ER应激的诱导减弱。NR 4A 1表达的操纵与基因表达谱分析相结合，鉴定了许多受NR 4A 1调控的ROS代谢转录物。这些转录本之一，含硫氧还蛋白结构域5（TXNDC 5）的敲低，重现了升高的ROS和ER应激;因此，表明NR 4A 1调节胰腺癌细胞中的ER应激和ROS水平，以促进细胞增殖和存活。最后，通过敲低或DIM-C-pPhOH使NR 4A 1失活降低TXNDC 5，导致ROS/ER应激和促凋亡途径的激活。
NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNAi interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and ER stress by these agents was attenuated after co-treatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and ER stress; thus, demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of ROS/ER stress and pro-apoptotic pathways.