title: 4EGI-1 induces apoptosis and enhances radiotherapy sensitivity in nasopharyngeal carcinoma cells via DR5 induction on 4E-BP1 dephosphorylation.
abstract: The eIF4F complex regulated by a various group of eIF4E-binding proteins (4E-BPs) can initial the protein synthesis. Small molecule compound 4EGI-1, an inhibitor of the cap-dependent translation initiation through disturbing the interaction between eIF4E and eIF4G which are main elements of the eIF4E complex, has been reported to suppress cell proliferation by inducing apoptosis in many types of cancer. And death receptor 5 (DR5) is a major component in the extrinsic apoptotic pathway. However, the correlation among 4EGI-1, DR5 and 4E-BPs have not been discovered in NPC now. Therefore, we intend to find out the effect of 4EGI-1 on the apoptosis process of NPC and the relationship among 4EGI-1, DR5 and 4E-BPs. Our results revealed a significant down regulation of DR5 expression in NPC tissues, which inversely correlated with lymph node metastasis status and clinical stages. Depressed DR5 expression was an independent biomarker for poor prognosis in NPC, and elevated DR5 expression showed longer overall survival time in 174 NPC patients. Besides, 4EGI-1 induced apoptosis in NPC cells through the DR5-caspase-8 axis on 4E-BP1 and eIF4E dephosphorylation exerting positive influence on their anti-tumor activities. The induction of DR5 also sensitized NPC cells to radiotherapy, and the SER was 1.195. These results establish the death receptor pathway as a novel anticancer mechanism of eIF4E/eIF4G interaction inhibitor in NPC.
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Qiuyuan
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jiadi
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Shuzhou
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Qing
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Mohannad Ma
authors.initials: MM
authors.lastname: Alnemah
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Songqing
authors.initials: S
authors.lastname: Fan
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C517852:4EGI-1 compound; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D006835:Hydrazones; D010750:Phosphoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles
keywords: 4EGI-1; DR5; apoptosis; nasopharyngeal carcinoma; radiotherapy