TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.
TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.
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DOI：
10.1038/s41388-020-01586-4
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Tanaka T
中科院分区：
文献类型：
--
作者：
Ochiiwa H;Ailiken G;Yokoyama M;Yamagata K;Nagano H;Yoshimura C;Muraoka H;Ishida K;Haruma T;Nakayama A;Hashimoto N;Murata K;Nishimura M;Kawashima Y;Ohara O;Ohkubo S;Tanaka T
TAS 4464是一种有效的选择性小分子NEDD 8激活酶（NAE）抑制剂，可导致cullin-RING E3泛素连接酶（CRL）失活，并导致其底物蛋白的累积。在这里，我们研究了TAS 4464在急性髓系白血病（AML）中的抗肿瘤特性和作用机制。TAS 4464在各种AML细胞系中诱导凋亡性细胞死亡。TAS 4464处理导致AML细胞中caspase-9介导的内源性凋亡途径和caspase-8介导的外源性凋亡途径活化;与这些caspase抑制剂联合处理显著减少了TAS 4464诱导的凋亡。在每个凋亡途径中，TAS 4464诱导内源性促凋亡因子NOXA的mRNA转录，并降低外源性抗凋亡因子c-FLIP的mRNA转录。RNA测序分析表明，TAS 4464处理后，CRL底物c-Myc的信号传导途径得到富集。染色质免疫沉淀（ChIP）试验显示，TAS 4464诱导的c-Myc与PMAIP 1（编码NOXA）和CFLAR（编码c-FLIP）启动子区域结合，siRNA介导的c-Myc敲低中和了TAS 4464介导的NOXA诱导和c-FLIP下调。TAS 4464激活半胱天冬酶-8和半胱天冬酶-9，同时沿着NOXA增加和c-FLIP减少，导致人AML异种移植模型中的肿瘤完全缓解。这些发现表明NAE抑制通过新的c-Myc依赖性凋亡诱导机制导致抗AML活性。
TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.
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通讯作者：
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作者：
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