Chen Ke, Yang Jianling, Li Jianning, Wang Xuefei, Chen Yuhai, Huang Shile, Chen Ji-Long
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China.
Oncotarget. 2016 Mar 1;7(9):10073-89. doi: 10.18632/oncotarget.7164.
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.
真核生物翻译起始因子4B（eIF4B）的激活与Abl介导的细胞转化相关，但具体机制尚不清楚。在此我们表明，eIF4B是Abl转化细胞中JAK/STAT/Pim和PI3K/Akt/mTOR信号通路的共同作用底物。这两条信号通路均可使Abl转化细胞中的eIF4B发生磷酸化，这种冗余调节导致单一抑制剂对Abl致癌性的抑制作用有限。持续抑制一条信号通路会诱导另一条信号通路的激活，从而恢复eIF4B的磷酸化水平。同时抑制这两条信号通路能更有效地削弱eIF4B的磷酸化，并协同诱导Abl转化细胞凋亡，抑制裸鼠体内移植瘤的生长。同样，当与基于短发夹RNA（shRNA）的另一条信号通路沉默相结合时，Abl转化细胞的存活对药物抑制表现出更高的敏感性。有趣的是，这种协同作用依赖于eIF4B第422位丝氨酸（Ser422）的磷酸化状态，因为在转化细胞中过表达eIF4B磷酸模拟突变体S422E可大大减弱这些抑制剂对Abl致癌性的协同作用。相反，敲低eIF4B可使Abl转化细胞对联合阻断诱导的凋亡更加敏感。总体而言，这些结果表明，eIF4B整合了Abl表达的白血病细胞中Pim和PI3K/Akt/mTOR信号通路的信号，是这类癌症有前景的治疗靶点。
