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Oncogene. 2014 Sep 11;33(37):4568-78. doi: 10.1038/onc.2014.32. Epub 2014 Mar 24.

Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy.

Author information

1
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.
2
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.
3
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.
4
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.
5
Clinical Biochemical Laboratory, Xiangya Hospital, Central South University, Changsha, China.
6
Pathology Department, Xiangya Hospital, Central South University, Changsha, China.
7
Pathology Department, The Second Xiangya Hospital, Central South University, Changsha, China.
8
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.
9
Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
10
Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha, China.
11
The Hormel Institute, University of Minnesota, Austin, MN, USA.
12
Center For Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.

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.

PMID:
24662831
PMCID:
PMC4162460
DOI:
10.1038/onc.2014.32
[Indexed for MEDLINE]
Free PMC Article

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