EIF4A1
EIF4E公司
基因沉默
生物
癌症研究
真核翻译
细胞周期
癌症
翻译(生物学)
信使核糖核酸
遗传学
基因
作者
Cailin E. Joyce,Adrienne G. Yanez,Akira Mori,Akinori Yoda,Johanna S. Carroll,Carl D. Novina
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2017-01-31
卷期号:77 (3): 613-622
被引量:23
标识
DOI:10.1158/0008-5472.can-16-1298
摘要
Abstract Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro. Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5′UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3′UTR. Moreover, their divergent effects occur through the 5′UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. Cancer Res; 77(3); 613–22. ©2016 AACR.
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