Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E.
Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E.
复制标题
DOI：
10.1158/0008-5472.can-16-1298
复制
发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Novina CD
中科院分区：
文献类型：
--
作者：
Joyce CE;Yanez AG;Mori A;Yoda A;Carroll JS;Novina CD
基于eIF4F帽结合复合物的这两个亚基在许多癌细胞中的频繁上调，已经探索了抑制翻译起始因子eIF4A1和eIF4E的小分子和反义寡核苷酸作为用于癌症治疗的基础广泛的治疗剂。在这里，我们提供了支持这些治疗方法的机制研究eIF4F驱动的肿瘤进展的黑色素瘤的临床前模型。沉默eIF4A1或eIF4E降低黑色素瘤增殖和侵袭。细胞周期蛋白水平的影响是共同的，这可以解释体外抗增殖作用。使用临床标本，我们将eIF4A1和eIF4E的共同细胞周期靶点与患者生存率相关联。最后，比较蛋白质组学和转录组学分析揭示了eIF4A1或eIF4E沉默的广泛机制分歧。目前的模型表明，eIF4A1和eIF4E通过5′UTR共同发挥作用，以增加癌基因的翻译。相反，我们的数据表明eIF4A1和eIF4E对翻译的共同作用是由编码区和3′UTR介导的。此外，它们的趋异效应通过5′UTR发生。总的来说，我们的工作表明，在不同的疾病背景下评估eIF4F的亚基特异性抑制剂以充分了解其抗癌作用将是重要的。
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 which 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.