title: Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy.
abstract: Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: L
authors.initials: L
authors.lastname: Xiao
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China [4] The First Hospital of Changsha City, Changsha, China.
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Hu
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: X
authors.initials: X
authors.lastname: Dong
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Tan
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China [4] Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: M
authors.initials: M
authors.lastname: Tang
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China [4] Center For Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Clinical Biochemical Laboratory, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: B
authors.initials: B
authors.lastname: Yi
authors.affiliation: Pathology Department, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Pathology Department, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: S
authors.initials: S
authors.lastname: Fan
authors.affiliation: 1] Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA [2] Endocrinology Department, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: S
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.affiliation: Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.affiliation: Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: L
authors.initials: L
authors.lastname: Feng
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Center For Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: L-Q
authors.initials: LQ
authors.lastname: Sun
authors.affiliation: 1] Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China [2] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China [3] Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
mesh_terms: D017209:Apoptosis; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005947:Glucose / Q000737:chemistry; D006019:Glycolysis; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D055432:Metabolomics; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000532:radiotherapy* / Q000821:virology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011838:Radiation-Sensitizing Agents; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016271:Proto-Oncogene Proteins c-myc; D011838:Radiation-Sensitizing Agents; D014763:Viral Matrix Proteins; D019344:Lactic Acid; D006593:Hexokinase; D005947:Glucose