发表在3月21日《化学与生物学》(Chemistry & Biology)封面上的最新一项研究,发现了两种新的抗癌化合物,它们能够致使含有RAS癌基因的癌细胞非程序性凋亡。
RAS是最常见的癌基因,它所编码的RAS蛋白是一种小G蛋白,其活性依赖与GTP的结合,突变的RAS蛋白质丧失了水解GTP的活性,从而激活RAS通路下游相关基因,导致细胞癌变。来自美国哥伦比亚大学的研究人员以RAS突变致癌的癌细胞为材料,通过联合致死筛选(synthetic lethal screening)的方法,从47725个人工合成或天然产物的衍生物中筛选出能致死该癌细胞的两种小分子化合物RSL3和RSL5。
联合致死的原理是:如果突变B特异性使具有突变A的细胞死亡,那么突变B即对突变A具有联合致死效应。基于该技术筛选出的RSL3和RSL5能够使含有RAS癌基因的细胞死亡,对其它细胞的无毒性或毒性很小,其中RSL3特异的使RAS癌基因的细胞死亡,而对其它细胞没有影响。
进一步研究发现,RSL3和RSL5的致死效应依赖于铁离子和RAS-RAF-MEK氧化作用。RNA干扰实验表明,线粒体内的压力依赖的阴离子通道(VDACs)参与了RSL5的致死过程,但与RSL3的致死作用无关。铁离子鳌合剂能同时抑制RSL5和RSL3诱导的癌细胞凋亡,表明铁离子在诱导细胞死亡过程中发挥了重要作用,而具有RAS癌基因的细胞能够通过上调铁传递蛋白受体1和下调铁蛋白的作用增家细胞内的铁含量。
传统的抗癌药物开发仅以单个癌基因相关蛋白为靶标,而本研究所采用的联合致死筛选方法则可以针对癌基因的作用方式进行药物筛选,具有更广泛的靶标,展现了比较好的药物开发前景,同时该方法也有利于进一步了解癌基因的作用机制。(科学网 穆宏平/编译)
生物谷推荐原始出处:
(Chemistry & Biology),Vol 15, 234-245, 21 March 2008,Wan Seok Yang and Brent R. Stockwell
Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells
Wan Seok Yang1 and Brent R. Stockwell1,2,
1 Department of Biological Sciences, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA
2 Department of Chemistry, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA
Corresponding author
Brent R. Stockwell
stockwell@biology.columbia.edu
Summary
We screened small molecules to identify two compounds, which we named RSL3 and RSL5, that have increased lethality in the presence of oncogenic RAS. Counter screening with biologically active compounds defined aspects of the mechanism of action for RSL3 and RSL5, such as a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death. Erastin, a previously reported compound with RAS-selective lethality, showed similar properties. RNA interference experiments targeting voltage-dependent anion channel 3 (VDAC3), a target of erastin, demonstrated that RSL5 is a scaffold that acts through VDACs to activate the observed pathway. RSL3 activated a similar death mechanism but in a VDAC-independent manner. We found that cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through upregulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.