The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth
The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth
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Nedd8 激活酶抑制剂 MLN4924 诱导自噬和细胞凋亡，从而抑制肝癌细胞的生长。
DOI：
10.1158/0008-5472.can-12-0388
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
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作者：
Luo, Zhongguang;Yu, Guangyang;Jia, Lijun
Cullin-Ring E3连接酶（CRL）复合物中Cullin的翻译后neddylation是CRL底物蛋白水解降解所必需的，其积累诱导细胞周期停滞、凋亡和衰老。Nedd 8激活酶（NAE）对于CRL复合物的neddylation及其生长促进功能至关重要。最近，目前处于I期试验中的抗癌小分子MLN 4924被确定为NAE的抑制剂，可阻断cullin neddylation并使CRL失活，从而引发CRL底物的蓄积，进而引发癌细胞的细胞周期停滞、细胞凋亡和衰老。在此，我们报告了MLN 4924也会触发自噬以响应CRL失活，并且该效应对于MLN 4924在体外和体内抑制肝癌细胞生长的能力非常重要。MLN 4924诱导的自噬部分归因于mTOR抑制蛋白Deptor蓄积导致的mTOR活性抑制以及活性氧应激诱导。抑制自噬可增强MLN 4924诱导的细胞凋亡，表明自噬是响应CRL失活而触发的存活信号。在人肝癌异种移植模型中，MLN 4924耐受性良好，并显示出显著的抗肿瘤作用，其特征为CRL失活以及诱导肝癌细胞的自噬和凋亡。总之，我们的研究结果支持MLN 4924用于肝癌治疗的临床研究，并为与自噬抑制剂联合治疗以增强疗效提供了临床前概念验证。
Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy.