Neddylation inhibition activates the extrinsic apoptosis pathway through ATF4-CHOP-DR5 axis in human esophageal cancer cells

Ping Chen, Tao Hu, Yupei Liang, Pei Li, Xiaoyu Chen, Jingyang Zhang, Yangcheng Ma, Qianyun Hao, Jinwu Wang, Ping Zhang, Yanmei Zhang, Hu Zhao, Shengli Yang, Jinha Yu, Lak Shin Jeong, Hui Qi, Meng Yang, Robert M. Hoffman, Ziming Dong, Lijun Jia

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


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 neddylationtargeted 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.

Original languageEnglish
Pages (from-to)4145-4157
Number of pages13
JournalClinical Cancer Research
Issue number16
StatePublished - 15 Aug 2016

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© 2016 AACR.


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