eIF4B is a convergent target and critical effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways in Abl transformants.
eIF4B is a convergent target and critical effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways in Abl transformants.
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eIF4B 是 Abl 转化体中致癌 Pim 和 PI3K/Akt/mTOR 信号通路的聚合靶标和关键效应子
DOI：
10.18632/oncotarget.7164
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发表时间：
2016-03-01
期刊：
影响因子：
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通讯作者：
Chen JL
中科院分区：
文献类型：
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作者：
Chen K;Yang J;Li J;Wang X;Chen Y;Huang S;Chen JL
eIF 4 B的激活与EIF介导的细胞转化相关，但确切的机制在很大程度上是未知的。在这里，我们表明eIF 4 B是Abl转化体中JAK/STAT/Pim和PI 3 K/Akt/mTOR途径的会聚底物。这两种途径都磷酸化EIF 4 B的EIF 4 B转化细胞，这种冗余的调节是负责有限的影响，单一抑制剂对Abl致癌性。持续抑制一个信号通路诱导另一个通路的激活，从而恢复eIF 4 B的磷酸化水平。同时抑制这两种途径更有效地损害eIF 4 B磷酸化，并协同诱导Abl转化细胞的凋亡，抑制裸鼠移植瘤的生长。类似地，当与另一途径的基于shRNA的沉默组合时，Abl转化体的存活表现出对药理学抑制的更高敏感性。有趣的是，这种协同作用依赖于eIF 4 B在Ser 422上的磷酸化状态，因为转化体中eIF 4 B磷酸模拟突变体S422 E的过表达极大地减弱了这些抑制剂对Abl致癌性的协同作用。相比之下，eIF 4 B敲低使Abl转化体敏感以经历由组合阻断诱导的细胞凋亡。总的来说，这些结果表明eIF 4 B整合了来自Pim和PI 3 K/Akt/mTOR通路的信号，并且是这种癌症的有希望的治疗靶点。
Activation of eIF4B correlates with Abl-mediated cellular transformation, but the precise mechanisms are largely unknown. Here we show that eIF4B is a convergent substrate of JAK/STAT/Pim and PI3K/Akt/mTOR pathways in Abl transformants. Both pathways phosphorylated eIF4B in Abl-transformed cells, and such redundant regulation was responsible for the limited effect of single inhibitor on Abl oncogenicity. Persistent inhibition of one signaling pathway induced the activation of the other pathway and thereby restored the phosphorylation levels of eIF4B. Simultaneous inhibition of the two pathways impaired eIF4B phosphorylation more effectively, and synergistically induced apoptosis in Abl transformed cells and inhibited the growth of engrafted tumors in nude mice. Similarly, the survival of Abl transformants exhibited a higher sensitivity to the pharmacological inhibition, when combined with the shRNA-based silence of the other pathway. Interestingly, such synergy was dependent on the phosphorylation status of eIF4B on Ser422, as overexpression of eIF4B phosphomimetic mutant S422E in the transformants greatly attenuated the synergistic effects of these inhibitors on Abl oncogenicity. In contrast, eIF4B knockdown sensitized Abl transformants to undergo apoptosis induced by the combined blockage. Collectively, the results indicate that eIF4B integrates the signals from Pim and PI3K/Akt/mTOR pathways in Abl-expressing leukemic cells, and is a promising therapeutic target for such cancers.