4EGI-1 induces apoptosis and enhances radiotherapy sensitivity in nasopharyngeal carcinoma cells via DR5 induction on 4E-BP1 dephosphorylation
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Weiyuan Wang1,*, Jiao Li1,*, Qiuyuan Wen1, Jiadi Luo1, Shuzhou Chu1, Lingjiao Chen1, Zhenzhen Qing2, Guiyuan Xie2, Lina Xu1, Mohannad Ma Alnemah1, Meirong Li1, Songqing Fan1, Hongbo Zhang1
1Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
2Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
*These authors have contributed equally to this work
Songqing Fan, e-mail: [email protected]
Hongbo Zhang, e-mail: [email protected]
Keywords: nasopharyngeal carcinoma, apoptosis, radiotherapy, 4EGI-1, DR5
Received: January 05, 2016 Accepted: February 21, 2016 Published: March 01, 2016
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.
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