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

许多遗传毒性药物通过诱导凋亡来杀死肿瘤细胞; 因此,抑制凋亡的突变会产生对化学疗法的抵抗力。尽管直接激活凋亡机制可能会绕过这些突变,但如何选择性地在癌细胞中实现这种激活尚不清楚。在这项研究中,我们表明抗药性293细胞系在用抗癌药物治疗后无法激活凋亡机制的成分-冰样蛋白酶 (caspases)。值得注意的是,来自未处理细胞的提取物会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,而且具有其激活剂。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,而正常细胞中不存在。我们提供了这种癌基因产生的活性 (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与细胞中的胱天蛋白酶联系起来的药物会杀死原本对常规癌症治疗具有抗性的肿瘤细胞。由于这种杀灭依赖于癌基因产生的活性,因此这些药物的作用应对转化细胞具有选择性。

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