EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma

• Published in: Cancer letters 2016-09, Vol.380 (1), p.191-200
• Main Authors: Lu, Jingchen, Li, Hongde, Xu, Zhijie, Tang, Min, Weng, Xinxian, Li, Jiangjiang, Yu, Xinfang, Zhao, Luqing, Liu, Hongwei, Hu, Yongbin, Yang, Lifang, Zhong, Meizuo, Zhou, Jian, Fan, Jia, Bode, Ann M, Yi, Wei, Gao, Jinghe, Sun, Lunquan, Cao, Ya
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apoptosis; Apoptosis - radiation effects; Carcinoma - enzymology; Carcinoma - pathology; Carcinoma - radiotherapy; Carcinoma - virology; Cell cycle; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA damage response; DNA Repair; DNA-Activated Protein Kinase - metabolism; DNA-PK; Dose-Response Relationship, Radiation; Enzyme Activation; Epstein-Barr virus; Epstein-Barr Virus Infections - virology; Female; Glycolysis; Hematology, Oncology and Palliative Medicine; Herpesvirus 4, Human - metabolism; Host-Pathogen Interactions; Humans; Immunoglobulins; Kinases; LMP1; Metabolism; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - enzymology; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - radiotherapy; Nasopharyngeal Neoplasms - virology; Nuclear Proteins - metabolism; Phosphorylation; Proteins; R&D; Radiation therapy; Radiation Tolerance; Research & development; Sensors; Signal Transduction - radiation effects; Time Factors; Tumor Burden - radiation effects; Viral Matrix Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2016.05.032

Highlights • A new mechanism for EBV-encoded LMP1-mediated radioresistance is proposed. • The mechanism relies on the suppression of DDR by LMP1 through inhibiting the DNA-PK/AMPK signaling pathway. • LMP1 impaired DSB repair in NPC cells induced by irradiation, possibly by inhibiting DNA-PK phosphorylation and activity. • The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. • The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro , which could provide a mechanistic rationale supporting the use of AMPK activators, such as metformin, for enhancing NPC radiotherapy.