Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells.
Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells.
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DOI：
10.1016/j.bcp.2012.02.021
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发表时间：
2012-05-15
影响因子：
5.8
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Li, Xi;Lee, Syng-Ook;Safe, Stephen
NR 4A 2（Nurr 1）是一种孤儿核受体，没有已知的内源性配体，在许多癌细胞系（包括Panc 1和Panc 28胰腺癌细胞）中高度表达。在用酵母GAL 4-Nurr 1嵌合体和UASx 5-luc报告基因或含有结合NR 4A 2的反应元件的构建体转染的胰腺癌细胞中，确定了一系列1，1-双（3′-吲哚基）-1-（芳香族）甲烷（C-DIM）类似物对NR 4A 2的结构依赖性激活。在23种结构类似物中，含有对位取代的三氟甲基、叔丁基、氰基、溴、碘和三氟甲氧基的苯基是反式激活活性最高的化合物。对溴苯基类似物（DIM-C-pPhBr）被用作一系列邻位、Meta位和对溴苯基异构体以及相应的吲哚2-和N-甲基类似物的结构-活性研究的模型。结果表明，NR 4A 2的活化是最大的对溴苯基类似物和吲哚NH基团的甲基化废除活性。此外，使用分别表达Nurr 1的N-和C-末端结构域的GAL 4-Nurr 1（全长）或GAL-Nurr 1-A/B和GAL 4-Nurr 1-（C-F）嵌合体，DIM-C-pPhBr激活所有三种构建体，并且这些反应受到激酶抑制剂的不同影响。DIM-C-pPhBr还调节胰腺癌细胞中包括血管活性肠肽（VIP）在内的几个Nurr 1调节基因的表达，免疫组织化学和蛋白质印迹分析表明DIM-C-pPhBr激活核NR 4A 2。
NR4A2 (Nurr 1) is an orphan nuclear receptor with no known endogenous ligands and is highly expressed in many cancer cell lines including Panc1 and Panc28 pancreatic cancer cells. Structure-dependent activation of NR4A2 by a series of 1,1-bis(3′-indolyl)-1-(aromatic)methane (C-DIM) analogs was determined in pancreatic cancer cells transfected with yeast GAL4-Nurr1 chimeras and a UASx5-luc reporter gene or constructs containing response elements that bind NR4A2. Among 23 different structural analogs, phenyl groups containing p-substituted trifluoromethyl, t-butyl, cyano, bromo, iodo and trifluoromethoxy groups were the most active compounds in transactivation assay. The p-bromophenyl analog (DIM-C-pPhBr) was used as a model for structure-activity studies among a series of ortho-, meta- and para-bromophenyl isomers and the corresponding indole 2- and N-methyl analogs. Results show that NR4A2 activation was maximal with the p-bromophenyl analog and methylation of the indole NH group abrogated activity. Moreover, using GAL4-Nurr1 (full length) or GAL-Nurr1-A/B and GAL4-Nurr1-(C-F) chimeras expressing N- and C-terminal domains of Nurr1, respectively, DIM-C-pPhBr activated all three constructs and these responses were differentially affected by kinase inhibitors. DIM-C-pPhBr also modulated expression of several Nurr1-regulated genes in pancreatic cancer cells including vasoactive intestinal peptide (VIP), and the immunohistochemical and western blot analyses indicated that DIM-C-pPhBr activates nuclear NR4A2.
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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：
11.2
作者：
Ke, N;Claassen, G;Li, QX
通讯作者：
Li, QX
影响因子：
4.7
作者：
Hermanson, Elisabet;Borgius, Lotta;Perlmann, Thomas
通讯作者：
Perlmann, Thomas
影响因子：
5.3
作者：
Luo, Yu;Henricksen, Leigh A.;Federoff, Howard J.
通讯作者：
Federoff, Howard J.
影响因子：
--
作者：
Lammi, J;Huppunen, J;Aarnisalo, P
通讯作者：
Aarnisalo, P