Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4-CHOP-DR5 Axis in Human Esophageal Cancer Cells
Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4-CHOP-DR5 Axis in Human Esophageal Cancer Cells
复制标题
Neddylation 抑制通过 ATF4-CHOP-DR5 轴激活人食管癌细胞的外源性凋亡途径
DOI：
10.1158/1078-0432.ccr-15-2254
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发表时间：
2016-08-15
影响因子：
11.5
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
--
作者：
Chen, Ping;Hu, Tao;Jia, Lijun
目的：靶向蛋白降解途径已成为一种有吸引力的抗癌策略，但死亡受体介导的外源性细胞凋亡在治疗过程中的作用仍有待确定。实验设计：在体内外评价外源性细胞凋亡的激活及其在MLN4924治疗人食管鳞癌(ESCC)中的作用。用免疫印迹法检测外源性细胞凋亡途径各组分的表达，并通过siRNA沉默机制研究。结果：药物或基因失活核糖核酸途径可诱导死亡受体5(DR5)介导的细胞凋亡，并抑制ESCC。从机制上讲，核苷酸抑制稳定了激活转录因子4(ATF4)，ATF4是库林环E3泛素连接酶(CRL)的底物。转录因子CHOP随后被ATF4反式激活，并进一步诱导DR5的表达，从而激活caspase-8并诱导外源性细胞凋亡。结论：我们的研究结果强调了ATF4-CHOP-DR5轴介导的外源性细胞凋亡在肾脏靶向癌症治疗中的关键作用，并支持了肾脏代谢抑制剂(如MLN4924)治疗ESCC的临床研究。ESCC是一种目前难以治疗的疾病。(C)2016年AACR。
Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined.Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.Conclusions: Our findings highlight a critical role of ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis in neddylation-targeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation. (C) 2016 AACR.