After exposure to cytotoxic chemotherapeutics, tumor cells alter their translatome to promote cell survival programs through the regulation of eukaryotic initiation factor 4F (eIF4F) and ternary complex. Compounds that block mTOR signaling and eIF4F complex formation, such as rapamycin and its analogs, have been used in combination therapies to enhance cell killing, although their success has been limited. This is likely because the cross-talk between signaling pathways that coordinate eIF4F regulation with ternary complex formation after treatment with genotoxic therapeutics has not been fully explored. Here, we described a regulatory pathway downstream of p53 in which inhibition of mTOR after DNA damage promoted cross-talk signaling and led to eIF2α phosphorylation. We showed that eIF2α phosphorylation did not inhibit protein synthesis but was instead required for cell migration and that pharmacologically blocking this pathway with either ISRIB or trazodone limited cell migration. These results support the notion that therapeutic targeting of eIF2α signaling could restrict tumor cell metastasis and invasion and could be beneficial to subsets of patients with cancer.

中文翻译：

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从mTOR到eIF2α的信号介导了细胞对阿霉素的化学反应。

暴露于细胞毒性化学治疗后，肿瘤细胞通过调节真核起始因子4F（eIF4F）和三元复合物来改变其跨膜组，从而促进细胞存活程序。阻断mTOR信号传导和eIF4F复合物形成的化合物，例如雷帕霉素及其类似物，已被用于联合疗法以增强细胞杀伤力，尽管它们的成功受到限制。这可能是因为尚未充分探讨在用遗传毒性治疗剂治疗后协调eIF4F调节与三元复合物形成的信号通路之间的相互影响。在这里，我们描述了p53下游的调控途径，其中DNA损伤后对mTOR的抑制促进了串扰信号传导并导致eIF2α磷酸化。我们显示，eIF2α磷酸化不会抑制蛋白质合成，但是是细胞迁移所必需的，并且药理作用是通过ISRIB或曲唑酮限制了该途径的细胞迁移。这些结果支持以下观点：治疗性靶向eIF2α信号传导可能会限制肿瘤细胞的转移和侵袭，并且可能有益于部分癌症患者。