ABT-263 诱导的 MCL1 上调依赖于人白血病细胞中自噬介导的 4EBP1 下调。
ABT-263-induced MCL1 upregulation depends on autophagy-mediated 4EBP1 downregulation in human leukemia cells.
机构信息
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
出版信息
Cancer Lett. 2018 Sep 28;432:191-204. doi: 10.1016/j.canlet.2018.06.019. Epub 2018 Jun 15.
The present study aimed to investigate the pathway related to MCL1 expression in ABT-263-treated human leukemia U937 cells. ABT-263 upregulated MCL1 protein expression but did not affect its mRNA level and protein stability. Notably, ABT-263 increased 4EBP1 mRNA decay and thus reduced 4EBP1 expression. Overexpression of 4EBP1 abrogated ABT-263-induced MCL1 upregulation. ABT-263-induced activation of IKKα/β-NFκB axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKKα/β-NFκB axis or autophagy mitigated the effect of ABT-263 on 4EBP1 and MCL1 expression. Amsacrine enhanced the cytotoxicity of ABT-263 in human leukemia U937, HL-60, and Jurkat cells because of its inhibitory effect on the IKKα/β-NFκB-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKKα/β-NFκB-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263.
本研究旨在探讨 ABT-263 处理人白血病 U937 细胞中与 MCL1 表达相关的途径。ABT-263 上调 MCL1 蛋白表达，但不影响其 mRNA 水平和蛋白稳定性。值得注意的是，ABT-263 增加了 4EBP1 mRNA 的降解，从而降低了 4EBP1 的表达。4EBP1 的过表达消除了 ABT-263 诱导的 MCL1 上调。ABT-263 诱导的 IKKα/β-NFκB 轴的激活引发了 U937 细胞的自噬，导致 4EBP1 的 mRNA 稳定性降低。抑制 IKKα/β-NFκB 轴或自噬减轻了 ABT-263 对 4EBP1 和 MCL1 表达的影响。安吖啶通过抑制 IKKα/β-NFκB 介导的途径，增强了 ABT-263 在人白血病 U937、HL-60 和 Jurkat 细胞中的细胞毒性。我们的数据表明，ABT-263 通过 IKKα/β-NFκB 介导的自噬诱导，减轻了 4EBP1 对 MCL1 蛋白合成的抑制作用，这为改善 ABT-263 的抗白血病治疗提供了一种有前途的策略。
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