TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1
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TNFAIP8通过与Rac1相互作用激活ERK信号通路促进AML化疗耐药
DOI：
10.1186/s13046-020-01658-z
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发表时间：
2020-08-14
影响因子：
11.3
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
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作者：
Pang, Yihua;Zhao, Yanan;Ji, Chunyan
化疗耐药已成为急性髓性白血病（AML）成功治疗的主要障碍，而逃避细胞凋亡是其基本机制之一。因此，揭开驱动这一过程的分子网络构成了一个迫切的未满足的需求。在此，我们的目的是表征肿瘤坏死因子诱导蛋白8 (TNFAIP8)，一种新的抗凋亡分子，在AML化疗耐药中的作用和分子机制。方法采用RT-qPCR和western blots检测AML患者及细胞系中TNFAIP8的表达水平。采用荧光素酶报告基因法、ChIP和RT-qPCR分析TNFAIP8的转录调控。通过功能实验评价TNFAIP8对AML细胞凋亡、药物敏感性和增殖的影响。western blots检测TNFAIP8对细胞外信号调节激酶（ERK）通路激活的潜在影响。通过CoIP和p21活化激酶（PAK）下拉实验确定上游靶点。在小鼠模型中检测了TNFAIP8对AML的总体影响。结果在AML患者和细胞系中首次证实了TNFAIP8的高调控表达。然后确定E74样ETS转录因子1 （ELF1）有助于其异常表达。通过控制TNFAIP8的表达，我们描述了其在保护AML细胞免受化疗药物诱导的凋亡和促进耐药中的作用。值得注意的是，TNFAIP8的促白血病作用是通过与Rac家族小GTPase 1 （Rac1）的相互作用来维持ERK信号通路的活性来介导的。此外，体内实验证实，抑制TNFAIP8可降低白血病浸润，提高生存率。结论我们的数据为TNFAIP8在AML化疗耐药和进展中的作用提供了分子基础，并突出了TNFAIP8作为一个有吸引力的治疗靶点的独特功能。
BackgroundChemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance.MethodsThe expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models.ResultsUpregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival.ConclusionOur data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.