The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53.
The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53.
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DOI：
10.1038/onc.2011.504
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发表时间：
2012-07-05
期刊：
影响因子：
8
通讯作者：
Safe, S.
中科院分区：
文献类型：
--
作者：
Lee, S-O;Andey, T.;Jin, U-H;Kim, K.;Sachdeva, M.;Safe, S.
孤儿核受体TR 3（NR 41 A，Nur 77）在大多数肺癌患者中过表达，是患者生存的负面预后因素。在非小细胞肺癌A549和H460细胞中研究了TR 3的功能，通过RNA干扰（siTR 3）敲低TR 3抑制癌细胞生长并诱导凋亡。TR 3的促生存活性部分是由于形成了p300/TR 3/Sp1复合物，该复合物与生存素和其他Sp1调节基因的富含GC的启动子区域结合（机制1）。然而，在p53野生型A549和H460细胞中，siTR 3抑制mTORC 1通路，这是由于p53的激活和p53应答基因sestrin 2的诱导，后者随后激活mTORC 1抑制剂AMPKα（机制2）。这表明TR 3在肺癌细胞中的促癌活性是由于p53的抑制和mTORC 1的激活。1，1-二（3′-吲哚基）-1-（对羟基苯基）甲烷（DIM-C-pPhOH）是最近发现的一种TR 3抑制剂，它模拟siTR 3的作用。DIM-C-pPhOH在小鼠原位和转移模型中抑制肺癌细胞和肺肿瘤的生长并诱导凋亡，并且这伴随着生存素表达的降低和mTORC 1信号传导的抑制，表明TR 3的灭活剂代表一类新型的mTORC 1抑制剂。
The orphan nuclear receptor TR3 (NR41A, Nur77) is overexpressed in most lung cancer patients and is a negative prognostic factor for patient survival. The function of TR3 was investigated in non-small cell lung cancer A549 and H460 cells, and knockdown of TR3 by RNA interference (siTR3) inhibited cancer cell growth and induced apoptosis. The prosurvival activity of TR3 was due, in part, to formation of a p300/TR3/Sp1 complex bound to GC-rich promoter regions of survivin and other Sp-regulated genes (mechanism 1). However, in p53 wild-type A549 and H460 cells, siTR3 inhibited the mTORC1 pathway and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2 which subsequently activated the mTORC1 inhibitor AMPKα (mechanism 2). This demonstrates that the pro-oncogenic activity of TR3 in lung cancer cells was due to inhibition of p53 and activation of mTORC1. 1,1-Bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) is a recently discovered inhibitor of TR3 which mimics the effects of siTR3. DIM-C-pPhOH inhibited growth and induced apoptosis in lung cancer cells and lung tumors in murine orthotopic and metastatic models, and this was accompanied by decreased expression of survivin and inhibition of mTORC1 signaling, demonstrating that inactivators of TR3 represent a novel class of mTORC1 inhibitors.
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影响因子：
11.2
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