Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4-CHOP-DR5 Axis in Human Esophageal Cancer Cells.

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 16 Pg. 4145-57 (Aug 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26983464 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• BH3 Interacting Domain Death Agonist Protein
• Biomarkers
• Cyclopentanes
• DDIT3 protein, human
• Pyrimidines
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Activating Transcription Factor 4
• Transcription Factor CHOP
• CASP8 protein, human
• Caspase 8
• pevonedistat

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Apoptosis (drug effects, genetics)
• BH3 Interacting Domain Death Agonist Protein (metabolism)
• Biomarkers
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cyclopentanes (pharmacology)
• Disease Models, Animal
• Esophageal Neoplasms (drug therapy, metabolism, mortality, pathology)
• Gene Silencing
• Humans
• Mice
• Models, Biological
• Prognosis
• Pyrimidines (pharmacology)
• RNA Interference
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor CHOP (metabolism)
• Xenograft Model Antitumor Assays