Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo
Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo
复制标题
阻断neddylation修饰可刺激体外肿瘤球形成以及体内干细胞分化和伤口愈合
DOI：
10.1073/pnas.1522367113
复制
发表时间：
2016
影响因子：
11.1
通讯作者：
Sun Yi
中科院分区：
文献类型：
--
作者：
Zhou Xiaochen;Tan Mingjia;Nyati Mukesh K.;Zhao Yongchao;Wang Gongxian;Sun Yi
MLN 4924是一种有效的NEDD 8激活酶小分子抑制剂，可通过抑制cullin neddylation来阻断cullin-RING连接酶活性。MLN 4924广泛用于临床前和临床环境中的抗癌应用。我们在此报告了一项意外发现：纳摩尔浓度的MLN 4924在肿瘤和正常干细胞模型中刺激干细胞增殖、自我更新和分化，并在小鼠模型中促进皮肤伤口愈合和体外细胞迁移。机制研究表明，MLN 4924导致c-MYC积聚并促进EGFR（表皮生长因子受体）二聚化以激活EGFR信号通路。我们的研究引起了对MLN 4924抗癌应用的关注，但同时为MLN 4924作为干细胞治疗和组织再生药物的未来开发提供了机会。MLN 4924也称为pevonedistat，是NEDD 8激活酶的首个同类抑制剂，可阻断蛋白质的整个neddylation修饰。以前的临床前研究和目前的临床试验一直专注于其抗癌特性。出乎意料的是，据我们所知，我们在此首次发现，当MLN 4924以纳摩尔浓度给药时，可显著刺激人癌细胞和小鼠胚胎干细胞的体外肿瘤球形成和体内肿瘤发生和分化。这些刺激作用可归因于（i）c-MYC通过阻断其降解而积累，以及（ii）EGFR（表皮生长因子受体）及其下游途径（包括PI 3 K/AKT/雷帕霉素的哺乳动物靶标和RAS/RAF/MEK/ERK）通过诱导EGFR二聚化而持续活化。最后，MLN 4924可加速小鼠EGF介导的皮肤伤口愈合，并在体外培养环境中刺激细胞迁移。综合这些数据，我们的研究表明，neddylation修饰可调节干细胞增殖和分化，低剂量MLN 4924可能对干细胞治疗和组织再生具有治疗价值。
Significance MLN4924, a potent small-molecule inhibitor of NEDD8-activating enzyme, blocks cullin-RING ligase activity through inhibiting cullin neddylation. MLN4924 is widely used in both preclinical and clinical settings for an anticancer application. We report here an unexpected finding: MLN4924 at nanomolar concentration stimulates stem cell proliferation, self-renewal, and differentiation in both tumor and normal stem cell models and promotes skin wound healing in a mouse model and cell migration in vitro. Mechanistic studies revealed that MLN4924 causes c-MYC accumulation and promotes EGFR (epidermal growth factor receptor) dimerization to activate the EGFR signaling pathway. Our study raises a concern in anticancer application of MLN4924, but at the same time provides an opportunity for future development of MLN4924 as an agent for stem cell therapy and tissue regeneration. MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration.