文章：

通过靶向抑制真核起始因子4A修饰化疗反应

Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A

原文发布日期：2013-07-19

DOI: 10.1038/bcj.2013.25

类型: Original Article

开放获取: 是

英文摘要：

Translation is regulated predominantly at the initiation phase by several signal transduction pathways that are often usurped in human cancers, including the PI3K/Akt/mTOR axis. mTOR exerts unique administration over translation by regulating assembly of eukaryotic initiation factor (eIF) 4F, a heterotrimeric complex responsible for recruiting 40S ribosomes (and associated factors) to mRNA 5′ cap structures. Hence, there is much interest in targeted therapies that block eIF4F activity to assess the consequences on tumor cell growth and chemotherapy response. We report here that hippuristanol (Hipp), a translation initiation inhibitor that selectively inhibits the eIF4F RNA helicase subunit, eIF4A, resensitizes Eμ-Myc lymphomas to DNA damaging agents, including those that overexpress eIF4E—a modifier of rapamycin responsiveness. As Mcl-1 levels are significantly affected by Hipp, combining its use with the Bcl-2 family inhibitor, ABT-737, leads to a potent synergistic response in triggering cell death in mouse and human lymphoma and leukemia cells. Suppression of eIF4AI using RNA interference also synergized with ABT-737 in murine lymphomas, highlighting eIF4AI as a therapeutic target for modulating tumor cell response to chemotherapy.

摘要翻译： 

翻译主要在起始阶段受到多种信号传导通路的调控，这些通路在人类癌症中常被异常利用，包括PI3K/Akt/mTOR轴。mTOR通过调控真核起始因子4F（eIF4F）的组装对翻译过程施加独特管控——eIF4F是一种异源三聚体复合物，负责将40S核糖体（及相关因子）招募至mRNA的5'端帽结构。因此，针对阻断eIF4F活性以评估其对肿瘤细胞生长和化疗反应影响的靶向治疗备受关注。本研究报道，马兜铃醇（Hipp）作为一种选择性抑制eIF4F RNA解旋酶亚基eIF4A的翻译起始抑制剂，能使Eμ-Myc淋巴瘤对DNA损伤剂（包括那些过表达雷帕霉素反应调节因子eIF4E的淋巴瘤）重新敏感。由于Mcl-1蛋白水平受Hipp显著影响，将其与Bcl-2家族抑制剂ABT-737联用，可在小鼠及人类淋巴瘤和白血病细胞中引发显著的协同效应，促使细胞死亡。通过RNA干扰抑制eIF4AI同样与ABT-737在鼠淋巴瘤中产生协同作用，这凸显了eIF4AI作为调控肿瘤细胞化疗反应的潜在治疗靶点。

原文链接：

Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A