Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues.
Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues.
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DOI：
10.1158/0008-5472.can-08-1972
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Zeng JZ
中科院分区：
文献类型：
--
作者：
Liu J;Zhou W;Li SS;Sun Z;Lin B;Lang YY;He JY;Cao X;Yan T;Wang L;Lu J;Han YH;Cao Y;Zhang XK;Zeng JZ
紫草素类化合物是紫草属植物紫草的有效成分，具有诱导细胞凋亡等多种生物学作用，其机制尚未明确。我们最近发现，孤儿核受体Nur77从细胞核迁移到线粒体，在线粒体上与Bcl2结合，诱导细胞凋亡。在此，我们报道了某些紫草素衍生物可以通过增加Nur77蛋白的水平并促进其在癌细胞中的线粒体靶向性来调节Nur77-Bcl2的凋亡途径。乙酰紫草素的结构修饰导致了一种衍生物5，8-diacetoxyl-6-(1‘-Acetoxyl-4’-methyl-3‘-pentenyl)-1，4-naphthaquinones(SK07)的鉴定，该衍生物在激活该途径方面表现出更高的有效性和特异性。与其他Nur77调节剂不同，shikonins通过其转录后调节增加Nur77蛋白的水平。SK07在Nur77基因敲除细胞中的凋亡作用被削弱，并被抑制Nur77胞质定位的软霉素B(LMB)共同处理而抑制。此外，SK07可诱导表达Nur77蛋白C末端一半的细胞凋亡，但不能诱导其N末端区域的凋亡。我们的数据还表明，SK07诱导的细胞凋亡与Bcl2构象的改变和Bax的激活有关。综上所述，我们的结果表明，某些紫草素衍生物作为Nur77介导的凋亡途径的调节器，并识别了新的以紫草素为基础的以Nur77为靶点的诱导细胞凋亡的铅。
Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that orphan nuclear receptor Nur77 migrates from the nucleus to mitochondria, where it binds to Bcl-2 to induce apoptosis. Here, we report that certain shikonin derivatives could modulate the Nur77-Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of acetylshikonin resulted in identification of a derivative 5,8-diacetoxyl-6-(1'-Acetoxyl-4'-methyl-3'-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by co-treatment with leptomycin B (LMB) that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the C-terminal half of Nur77 protein but not its N-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results demonstrate that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify new shikonin-based lead that targets Nur77 for apoptosis induction.