期刊
JOURNAL OF BIOMOLECULAR SCREENING
卷 18, 期 4, 页码 407-419出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057112466698
关键词
translation regulation; internal ribosome entry site; c-Myc; VEGF; EMCV; high-throughput screening
资金
- Novartis Institutes of Biomedical Research
- NIBR Education Office
Translation initiation is a fine-tuned process that plays a critical role in tumorigenesis. The use of small molecules that modulate mRNA translation provides tool compounds to explore the mechanism of translational initiation and to further validate protein synthesis as a potential pharmaceutical target for cancer therapeutics. This report describes the development and use of a click beetle, dual luciferase cell-based assay multiplexed with a measure of compound toxicity using resazurin to evaluate the differential effect of natural products on cap-dependent or internal ribosome entry site (IRES)-mediated translation initiation and cell viability. This screen identified a series of cardiac glycosides as inhibitors of IRES-mediated translation using, in particular, the oncogene mRNA c-Myc IRES. Treatment of c-Myc-dependent cancer cells with these compounds showed a decrease in c-Myc protein associated with a significant modulation of cell viability. These findings suggest that inhibition of IRES-mediated translation initiation may be a strategy to inhibit c-Myc-driven tumorigenesis.
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