Inhibition of the Translation Initiation Factor eIF4A Enhances Tumor Cell Radiosensitivity.
Inhibition of the Translation Initiation Factor eIF4A Enhances Tumor Cell Radiosensitivity.
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DOI：
10.1158/1535-7163.mct-22-0037
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发表时间：
2022-09-06
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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细胞放射反应的一个基本组成部分是基因表达的翻译控制。由于翻译控制的关键调节因子是eIF 4F帽结合复合物，我们研究了eIF 4A（eIF 4F的RNA解旋酶组分）是否可以作为放射增敏的靶点。使用siRNA敲低eIF 4A降低了翻译效率，如从多核糖体谱测定的，并且增强了肿瘤细胞的放射敏感性，如通过克隆形成存活测定的。放射敏感性的增加伴随着辐射诱导的γ H2 AX灶的延迟分散，表明DNA双链断裂修复的抑制。研究随后扩展到（−）-SDS-1-021，一种eIF 4A的药理学抑制剂。用rocaglate（−）-SDS-1-021处理细胞导致翻译效率和蛋白质合成降低。（−）-SDS-1-021处理还增强了肿瘤细胞系的放射敏感性。这种（−）-SDS-1-021诱导的放射增敏伴随着辐射诱导的γ H2 AX灶分散延迟，与抑制双链断裂修复的原因作用一致。相反，虽然（−）-SDS-1-021抑制正常成纤维细胞系中的翻译和蛋白质合成，但对正常细胞的放射敏感性没有影响。然后使用皮下异种移植物评价对（−）-SDS-1-021和辐射的体内反应。用（−）-SDS-1-021处理携带皮下异种移植物的小鼠降低了肿瘤的翻译效率，这通过多核糖体谱测定。虽然（−）-SDS-1-021单独处理对肿瘤生长没有影响，但它显著增强了辐射诱导的生长延迟。这些结果表明eIF 4A是放射增敏的肿瘤选择性靶点。
A fundamental component of cellular radioresponse is the translational control of gene expression. As a critical regulator of translational control is the eIF4F cap binding complex, we investigated whether eIF4A, the RNA helicase component of eIF4F, can serve as a target for radiosensitization. Knockdown of eIF4A using siRNA reduced translational efficiency, as determined from polysome profiles, and enhanced tumor cell radiosensitivity as determined by clonogenic survival. The increased radiosensitivity was accompanied by a delayed dispersion of radiation-induced γH2AX foci, suggestive of an inhibition of DNA double strand break repair. Studies were then extended to (−)-SDS-1-021, a pharmacological inhibitor of eIF4A. Treatment of cells with the rocaglate (−)-SDS-1-021 resulted in a decrease in translational efficiency as well as protein synthesis. (−)-SDS-1-021 treatment also enhanced the radiosensitivity of tumor cell lines. This (−)-SDS-1-021-induced radiosensitization was accompanied by a delay in radiation-induced γH2AX foci dispersal, consistent with a causative role for the inhibition of double strand break repair. In contrast, while (−)-SDS-1-021 inhibited translation and protein synthesis in a normal fibroblast cell line, it had no effect on radiosensitivity of normal cells. Subcutaneous xenografts were then used to evaluate the in vivo response to (−)-SDS-1-021 and radiation. Treatment of mice bearing subcutaneous xenografts with (−)-SDS-1-021 decreased tumor translational efficiency as determined by polysome profiles. While (−)-SDS-1-021 treatment alone had no effect on tumor growth, it significantly enhanced the radiation-induced growth delay. These results suggest that eIF4A is a tumor selective target for radiosensitization.
4EGI-1通过DR5诱导4E-BP1去磷酸化诱导鼻咽癌细胞凋亡并增强放疗敏感性
影响因子：
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作者：
Wang W;Li J;Wen Q;Luo J;Chu S;Chen L;Qing Z;Xie G;Xu L;Alnemah MM;Li M;Fan S;Zhang H
通讯作者：
Zhang H