Oncogene-dependent apoptosis in extracts from drug-resistant cells.
HO Fearnhead, ME McCurrach, J O'Neill… - Genes & …, 1997 - genesdev.cshlp.org
HO Fearnhead, ME McCurrach, J O'Neill, K Zhang, SW Lowe, YA Lazebnik
Genes & development, 1997•genesdev.cshlp.orgMany 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 …
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 …
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.
genesdev.cshlp.org
以上显示的是最相近的搜索结果。 查看全部搜索结果