American Association for Cancer Research
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supplemental legend from Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

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posted on 2023-03-31, 18:14 authored by 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

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Funding

National Basic Research Program of China

National Natural Science Foundation of China

Shanghai Education Development Foundation

Youth Scholars of Zhengzhou University, and Research Foundation of Education Bureau of Henan Province, China

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ARTICLE ABSTRACT

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. Clin Cancer Res; 22(16); 4145–57. ©2016 AACR.