厦大张晓坤Cancer Research又发抗癌成果文章

生物通报道，厦门大学张晓坤教授自10月7号在Cell子刊Cancer Cell发表文章发现神奇抗癌小肽后（详细报道参见：厦大张晓坤Cancer Cell发表癌症突破性成果）http://www.ebiotrade.com/newsf/2008-10/2008108161717.htm，11月1日又在Cancer Research （影响因子：7.672）发表抗癌研究新成果。

　　

癌小肽后（详细报道参见：厦大张晓坤Cancer Cell发表癌症突破性成果）http://www.ebiotrade.com/newsf/2008-10/2008108161717.htm，11月1日又在Cancer Research （影响因子：7.672）发表抗癌研究新成果。

 

该研究由厦门大学生物医学研究院曾锦章教授和张晓坤教授共同主持。研究小组发现一种紫草素的衍生物可敏感地调控肿瘤细胞中的Nur77/Bcl-2诱导的细胞凋亡通路。该文的第一作者是他们的博士生刘婕同学。曾锦章教授和张晓坤教授为该文的共同通讯作者，他们共同设计和指导了有关实验，并共同撰写了该文章。

 

紫草素及衍生物是从中国传统中草药紫草中分离出来的一类活性化合物。数千年来，人们就用这种草药治疗各种皮肤疾病，局部用药有助于皮肤烧伤和慢性溃疡的愈合。这类化合物具有很好的消炎和抗肿瘤作用，但由于毒性较大，一直无法真正地应用于临床。该课题组利用他们近年来发现的一条抗肿瘤通道Nur77/Bcl-2的分子模型对中国中草药的有效成分进行筛选，基于这一分子模型，他们改进了紫草素的结构，使其能更特异地启动这一死亡通路。

 

紫草素通过转录后调控作用提高Nur77蛋白的表达水平，通过Nur77/Bcl2通路促进癌细胞进入细胞凋亡程序。

 

该课题受到国家863、国家自然科学基金、上海市重大项目、福建省科技计划重点研究项目以及美国国立卫生研究院（NIH）项目的支持。

 

原文检索：Modulation of Orphan Nuclear Receptor Nur77-Mediated Apoptotic Pathway by Acetylshikonin and Analogues

 

【Abstract】

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 the 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 the 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 the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH₂-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction.

生物通 张欢