Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action
Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action
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DOI：
10.1210/me.2005-0186
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发表时间：
2006-03-01
影响因子：
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通讯作者：
Katzenellenbogen, BS
中科院分区：
文献类型：
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作者：
Harrington, WR;Kim, SH;Katzenellenbogen, BS
雌激素通常被认为是通过与核雌激素受体结合和改变靶基因转录来发挥作用的，但雌激素也可以通过快速激活膜启动的激酶级联反应来发挥非基因组效应。只选择性激活非基因组途径的配体的发展将为研究这些途径的意义提供有用的工具。我们已经制备了大的、非生物的、不可降解的聚(氨基)胺树枝状大分子，它们通过化学上的强键连接到多个雌激素分子上。由于它们的电荷和大小，这些雌激素-树枝状大分子结合物(EDCs)留在细胞核外。它们在低浓度时刺激MCF-7乳腺癌细胞ERK、Shc和Src的磷酸化，但在刺激内源性雌激素靶基因的转录方面非常无效，在基因组作用上大约比雌二醇低10,000倍。与雌二醇相比，EDC不能有效地刺激乳腺癌细胞的增殖。由于这些EDC配体在不改变雌激素靶基因转录的浓度下激活非基因组活性，它们应该有助于研究在各种靶细胞中启动的雌激素作用的核外途径。
Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido) amine dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages. Because of their charge and size, these estrogen-dendrimer conjugates (EDCs) remain outside the nucleus. They stimulate ERK, Shc, and Src phosphorylation in MCF-7 breast cancer cells at low concentrations, yet they are very ineffective in stimulating transcription of endogenous estrogen target genes, being approximately 10,000-fold less potent than estradiol in genomic actions. In contrast to estradiol, EDC was not effective in stimulating breast cancer cell proliferation. Because these EDC ligands activate nongenomic activity at concentrations at which they do not alter the transcription of estrogen target genes, they should be useful in studying extranuclear initiated pathways of estrogen action in a variety of target cells.