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

L. Xiao, Z. Y. Hu, X. Dong, Z. Tan, W. Li, M. Tang, L. Chen, L. Yang, Y. Tao, Y. Jiang, J. Li, B. Yi, B. Li, S. Fan, S. You, X. Deng, F. Hu, L. Feng, A. M. Bode, Z. DongL. Q. Sun, Y. Cao

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4568-4578
Number of pages11
JournalOncogene
Volume33
Issue number37
DOIs
StatePublished - 2014

Bibliographical note

Funding Information:
We thank Dr Ryan Michalek, Dr Sheng Quan and Dr Lining Guo at Metabolon for metabolomics analysis. We also thank Dr Giovanni Melillo from Bristol-Myers Squibb for their critical comments and suggestions. This study was supported by National Basic Research Program of China, No. 2011CB504305; The National High Technology Research and Development Program of China, No. 2012AA02A501; National Natural Science Foundation of China (NSFC), No. 30930101 and 81161120410; and China Postdoctoral Science Foundation funded project, No. 2011M501300.

Publisher Copyright:
© 2014 Macmillan Publishers Limited All rights reserved.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy'. Together they form a unique fingerprint.

Cite this