1. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway.
- Author
-
Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, and Quon KC
- Subjects
- Animals, Caspase 8, Caspases metabolism, Fibroblasts metabolism, Gene Targeting, Humans, Male, Mice, Mice, Nude, Mice, SCID, Proto-Oncogene Proteins c-myc antagonists & inhibitors, Receptors, TNF-Related Apoptosis-Inducing Ligand, Retroviridae genetics, Transplantation, Heterologous, Tumor Cells, Cultured, Tumor Suppressor Protein p53 metabolism, Up-Regulation, Antineoplastic Agents pharmacology, Apoptosis, Mutation genetics, Proto-Oncogene Proteins c-myc physiology, RNA, Small Interfering pharmacology, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction
- Abstract
The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.
- Published
- 2004
- Full Text
- View/download PDF