WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia
WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia
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WP1130揭示USP24作为T细胞急性淋巴细胞白血病的新靶点
DOI：
10.1186/s12935-019-0773-6
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发表时间：
2019-03-13
影响因子：
5.8
通讯作者：
Wu, Yingli
中科院分区：
文献类型：
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作者：
Luo, Hao;Jing, Bo;Wu, Yingli
背景T细胞急性淋巴细胞白血病（T-ALL）是一种由未成熟T细胞祖细胞致癌转化引起的淋巴恶性肿瘤，预后较差。WP 1130对多种癌症显示出有效的活性，但WP 1130是否具有抗T-ALL活性尚不清楚。USP 24是WP 1130的一个靶标，是最大的去泛素化酶之一，其详细机制知之甚少。本研究的目的是探讨WP 1130是否可以抑制T-ALL和USP 24在T-ALL中的作用。方法采用分子对接和细胞热位移实验来确定WP 1130是否和如何与USP 24直接相互作用。通过罗丹明123染色测定线粒体跨膜电位。使用失活的CRISPR相关蛋白9（dCas 9）-协同活化介体（SAM）系统重新活化USP 24。通过NOD-SCID小鼠中的肿瘤异种移植物检查体内结果。结果WP 1130在体内外均能降低T-ALL细胞的存活率，诱导T-ALL细胞凋亡。此外，我们证明了USP 24而非USP 9 X的敲低可显著诱导T-ALL细胞的生长抑制和凋亡。Oncomine数据库显示USP 24在T-ALL样本中表达上调，Kaplan-Meier结果显示USP 24与T-ALL患者的生存率呈负相关，而USP 9 X与T-ALL患者的生存率呈正相关。此外，我们提出WP 1130直接与T-ALL细胞中USP 24的活性位点口袋相互作用，导致其底物Mcl-1的减少。从机制上讲，WP 1130通过加速线粒体跨膜电位的崩溃通过USP 24-Mcl-1 axis.ConclusionsAltogether诱导细胞凋亡，使用WP 1130作为化学探针，我们证明，USP 24，而不是USP 9 X是一个新的目标，在T-ALL细胞。此外，我们发现WP 1130通过USP 24-Mcl-1轴加速线粒体跨膜电位的崩溃来诱导细胞凋亡。这些结果表明，USP 24-Mcl-1轴可能代表了治疗T-ALL的新策略，WP 1130是开发抗T-ALL药物的有希望的先导化合物。
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors with poor outcomes. WP1130 has shown potent activity against a variety of cancer but whether WP1130 has anti-T-ALL activity is not clear. USP24, one target of WP1130, is one of the largest deubiquitinases and its detailed mechanism is poorly understood. The aim of this study was to explore whether WP1130 could suppress T-ALL and the role of USP24 in T-ALL.MethodsMolecular docking and cellular thermal shift assay were performed to determine whether and how WP1130 directly interact with USP24. Mitochondrial transmembrane potential assay was measured via Rhodamine 123 staining. USP24 was reactivated using the deactivated CRISPR-associated protein 9 (dCas9)-synergistic activation mediator (SAM) system. The in vivo results were examined by tumor xenografts in NOD-SCID mice. All statistical analyses were performed with the SPSS software package.ResultsWP1130 treatment decreased the viability and induces apoptosis of T-ALL cells both in vitro and in vivo. Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells. Oncomine database showed that USP24 expression was upregulated in T-ALL samples and Kaplan–Meier results indicated that the USP24 was negatively but USP9X was positively associated with survival in T-ALL patients. Additionally, we proposed that WP1130 directly interacts with the activity site pocket of USP24 in T-ALL cells, which leads to the decrease of its substrates Mcl-1. Mechanistically, WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis.ConclusionsAltogether, using WP1130 as a chemical probe, we demonstrate that USP24 but not USP9X is a novel target in T-ALL cells. Moreover, we uncovered that WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. These results provide that USP24-Mcl-1 axis may represent a novel strategy in the treatment of T-ALL and WP1130 is a promising lead compound for developing anti-T-ALL drugs.