title: Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4-CHOP-DR5 Axis in Human Esophageal Cancer Cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China. Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. ljjia@fudan.edu.cn dongzm@zzu.edu.cn zzdx_chenping@zzu.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Liang
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Yangcheng
authors.initials: Y
authors.lastname: Ma
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Qianyun
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Pathology, Linzhou Cancer Hospital, Linzhou, China.
authors.forename: Jinwu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Huadong Hospital; Shanghai Key Laboratory of Clinical Geriatric Medicine; Research Center on Aging and Medicine, Fudan University, Shanghai, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Huadong Hospital; Shanghai Key Laboratory of Clinical Geriatric Medicine; Research Center on Aging and Medicine, Fudan University, Shanghai, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jinha
authors.initials: J
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: AntiCancer Biotech (Beijing) Co., Ltd., Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qi
authors.affiliation: AntiCancer Biotech (Beijing) Co., Ltd., Beijing, China. Department of Surgery, University of California, San Diego, California. AntiCancer, Inc., San Diego, California.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: AntiCancer Biotech (Beijing) Co., Ltd., Beijing, China. Department of Surgery, University of California, San Diego, California. AntiCancer, Inc., San Diego, California.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China. ljjia@fudan.edu.cn dongzm@zzu.edu.cn zzdx_chenping@zzu.edu.cn.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. ljjia@fudan.edu.cn dongzm@zzu.edu.cn zzdx_chenping@zzu.edu.cn.
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015415:Biomarkers; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D015415:Biomarkers; D003517:Cyclopentanes; C497249:DDIT3 protein, human; D011743:Pyrimidines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C505530:CASP8 protein, human; D053181:Caspase 8; C539933:pevonedistat