RAS-RAF-MEK-依赖的氧化细胞死亡涉及电压依赖的离子通道
Nicholas Yagoda1, Moritz von Rechenberg, Elma Zaganjor
1Department of Biological Sciences, Fairchild Center, 1212 Amsterdam Avenue, MC 2406, New York, New York 10027, USA.
Nature
|June 15, 2007
概括
埃拉斯通过向线粒体VDAC蛋白质,选择性地杀死具有RAS-RAF-MEK途径突变的癌细胞,诱导氧化应激和非亡性细胞死亡. 这表明VDACs是新的抗癌药物标.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 生物化学 生物化学
背景情况:
- 针对性癌症治疗需要分辨正常细胞和瘤细胞的药物.
- 瘤基因选择性致死性为开发更有效,更少毒性的抗癌药物提供了一种战略.
- RAS-RAF-MEK信号通路对于细胞增殖,分化和生存至关重要,并且在癌症中经常发生突变.
研究的目的:
- 为了阐明选择性抗瘤剂erastin的作用机制.
- 为了确定癌症治疗的新型分子标.
- 研究RAS-RAF-MEK通路在埃拉斯抗癌活性中的作用.
主要方法:
- afinity 净化和质谱测试,以确定埃拉斯的结合伙伴.
- 细胞活力测试用于评估具有特定瘤突变的癌细胞中埃拉斯的致命性.
- 用RNA干扰来研究VDAC异型的作用.
- 线粒体透性测定.线粒体透性测定.
- 用放射性标记的埃拉斯进行过器结合测试.
主要成果:
- 埃拉斯对具有HRAS,KRAS或BRAF突变的人类瘤细胞具有选择性致死性.
- 埃拉斯针对线粒体的电压依赖离子通道 (VDACs).
- 埃拉斯在瘤性RAS表达细胞中诱导氧化物种和非亡性细胞死亡.
- 降低VDAC2和VDAC3可使人对埃拉斯产生抗性.
- 埃拉斯改变了线粒体外膜的透性,直接与VDAC2.2结合.
结论:
- 埃拉斯通过准VDAC蛋白来起作用,这是抗癌药物的一种新机制.
- 向VDAC蛋白的配体可以在瘤中诱导选择性的非亡细胞死亡,在RAS-RAF-MEK途径中激活突变.
- 这项研究确定了VDACs作为开发新型选择性癌症疗法的有希望的目标.
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