title: EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma.
abstract: We conducted this research to explore the role of latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus (EBV) in modulating the DNA damage response (DDR) and its regulatory mechanisms in radioresistance. Our results revealed that LMP1 repressed the repair of DNA double strand breaks (DSBs) by inhibiting DNA-dependent protein kinase (DNA-PK) phosphorylation and activity. Moreover, LMP1 reduced the phosphorylation of AMP-activated protein kinase (AMPK) and changed its subcellular location after irradiation, which appeared to occur through a disruption of the physical interaction between AMPK and DNA-PK. The decrease in AMPK activity was associated with LMP1-mediated glycolysis and resistance to apoptosis induced by irradiation. The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro. The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. Our data revealed a new mechanism of LMP1-mediated radioresistance and provided a mechanistic rationale in support of the use of AMPK activators for facilitating NPC radiotherapy.
authors.affiliation: Department of Medical Oncology, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Jingchen
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Hongde
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xinxian
authors.initials: X
authors.lastname: Weng
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Jiangjiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xinfang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China; Molecular Imaging Center, Central South University, Changsha, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Meizuo
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Chinese Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Chinese Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Jinghe
authors.initials: J
authors.lastname: Gao
authors.affiliation: Molecular Imaging Center, Central South University, Changsha, China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China; Molecular Imaging Center, Central South University, Changsha, China. Electronic address: ycao98@vip.sina.com.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy* / Q000821:virology; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000821:virology*; D005260:Female; D006019:Glycolysis; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy* / Q000821:virology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D047368:Tumor Burden / Q000528:radiation effects; D014763:Viral Matrix Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009687:Nuclear Proteins; D014763:Viral Matrix Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMPK; DNA damage response; DNA-PK; LMP1; Nasopharyngeal carcinoma