Translation initiation factor eIF4E is a target for tumor cell radiosensitization.
Translation initiation factor eIF4E is a target for tumor cell radiosensitization.
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DOI：
10.1158/0008-5472.can-12-0329
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发表时间：
2012-05-01
期刊：
影响因子：
11.2
通讯作者：
Tofilon PJ
中科院分区：
文献类型：
--
作者：
Hayman TJ;Williams ES;Jamal M;Shankavaram UT;Camphausen K;Tofilon PJ
细胞对辐射的反应的一个核心组成部分发生在基因表达的翻译控制水平上。由于翻译控制中的一个关键因素是启动因子eIF4E的可用性，它选择性地增强mRNAs的帽依赖翻译，因此我们研究了eIF4E在细胞辐射敏感性中的调节作用。EIF4E沉默增强了肿瘤细胞系的放射敏感性，但不能提高正常细胞的放射敏感性。同样，利巴韦林对eIF4E的药理抑制也增强了肿瘤细胞的放射敏感性。EIF4E衰减对细胞周期时相分布和辐射诱导的细胞凋亡没有影响，但它延迟了辐射诱导的γH_2AX焦点的分散，并增加了辐射诱导的有丝分裂突变的频率。辐射不影响4E-BP1的磷酸化或帽子复合体的形成，但它增加了eIF4E与>；1000独特转录本的结合，包括许多与DNA复制、重组和修复有关的转录本。综上所述，我们的发现表明eIF4E是一个合理的治疗靶点，可以提高肿瘤细胞的放射敏感性。
A core component in the cellular response to radiation occurs at the level of translational control of gene expression. Because a critical element in translation control is the availability of the initiation factor eIF4E, which selectively enhances the cap-dependent translation of mRNAs, we investigated a regulatory role for eIF4E in cellular radiosensitivity. eIF4E silencing enhanced the radiosensitivity of tumor cell lines but not normal cells. Similarly, pharmacological inhibition of eIF4E with ribavirin also enhanced tumor cell radiosensitivity. eIF4E attenuation did not affect cell cycle phase distribution or radiation-induced apoptosis, but it delayed the dispersion of radiation-induced γH2AX foci and increased the frequency of radiation-induced mitotic catastrophe. Radiation did not affect 4E-BP1 phosphorylation or cap-complex formation but it increased eIF4E binding to >1000 unique transcripts including many implicated in DNA replication, recombination and repair. Taken together, our findings suggest that eIF4E represents a logical therapeutic target to increase tumor cell radiosensitivity.