Oncogene-dependent apoptosis in extracts from drug-resistant 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.
Fearnhead
H O
HO
Cold Spring Harbor Laboratory, New York 11724, USA. fearnhea@cshl.org
McCurrach
M E
ME
O'Neill
J
J
Zhang
K
K
Lowe
S W
SW
Lazebnik
Y A
YA
D000255:Adenosine Triphosphate / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017502:Adenovirus E2 Proteins / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002474:Cell-Free System; D002852:Chromatography, Ion Exchange; D003546:Cysteine Endopeptidases / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004789:Enzyme Activation; D019254:Genes, bcl-2; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D009857:Oncogenes
D017500:Adenovirus E1A Proteins; D017502:Adenovirus E2 Proteins; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases