Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

译文

许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此,抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变,但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中,我们显示抗药性293细胞系无法激活抗凋亡药物ICE样蛋白酶(胱天蛋白酶)的凋亡机制的组成部分。值得注意的是,未经处理的细胞提取物可自发激活胱天蛋白酶并在无细胞系统中诱导凋亡,这表明耐药细胞不仅具有凋亡机制,还具有其激活剂。比较具有确定的遗传差异的细胞提取物,我们表明该激活剂是由腺病毒E1A癌基因产生的,而正常细胞中却不存在。我们提供了此致癌基因产生的活性(OGA)的初步表征,并表明当添加到未转化细胞的提取物中时,部分纯化的OGA会激活胱天蛋白酶。我们建议,将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞,否则它们会对常规的癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性,因此这些药剂对转化细胞的作用应该是选择性的。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录