Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy
Authors: S Fan
B Yi
L Chen
Z Tan
Z Dong
F Hu
L Feng
M Tang
S You
L Xiao
L Yang
W Li
A M Bode
L-Q Sun
Z-Y Hu
Y Cao
Y Jiang
Y Tao
X Deng
B Li
J Li
X Dong
Journal: Oncogene (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Epstein-Barr virus (EBV); nasopharyngeal carcinoma (NPC); glycolysis; metabolism; latent membrane protein 1 (LMP1)
Affiliations: 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., 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., 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., 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., Clinical Biochemical Laboratory, Xiangya Hospital, Central South University, Changsha, China., Pathology Department, Xiangya Hospital, Central South University, Changsha, China., Pathology Department, The Second Xiangya Hospital, Central South University, Changsha, China., 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., Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha, China., The Hormel Institute, University of Minnesota, Austin, MN, USA., 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. 

Retracted: No

PubPeer comments:
 Figure 7c. Much more similar than you would expect after a horizontal flip. https: imgur.com 0O0OWSs , 
 Figure 2. Much more similar than you would expect (slightly different exposures). https: imgur.com ztfWjYg , 
 Hi Opisthostoma Senex, This is Lun-quan Sun from Central South University, also the co-corresponding author of this Oncogene paper. First of all, we thank you for your interests in this paper, and highly appreciated your diligent and careful examining of our paper. We do review the points you brought up at PUBPEER, and here are our point-to-point responses to your comments. 1. In Figure 7C, we found out that we unintentionally used the same actin blot pic twice, and we have attached our original blot here. It clearly showed that we did the actin western blot for both four blots, however, we mistakenly used the same actin blot twice when Lanbo preparing the figures for the manuscript submission.  2. It seems that you suggested that there was a picture manipulation in Figure 2C and Figure 2D. We reviewed our record, and here is the original blot of this experiment. It clearly demonstrated that we did separately western blots for Figure 2C and Figure 2D, and thereu2019s no picture manipulation. To sum, we do appreciate your concerns regarding our paper, and apologize for any confusion or inconvenience that this oversight may have caused. However, we do not think such unintentional mistake would affect the conclusion of our paper, and we will review our figures , 
 more carefully for our future publications. In the meanwhile, we are contacting with editors at Oncogene to see if any correction is necessary based upon the issue your brought up. ,