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

Xiao, Lanbo; Hu, Zhilan; Dong, Xin; Tan, Zhongping; Li, W.; Tang, Min; Chen, L.; Yang, Lifang; Tao, Yongguang; Jiang, Yiqun; Li, J.; Yi, Bin; Li, B.; Fan, Songqing; You, Sylvaine; Deng, Xingming; Hu, Fang; Feng, Li; Bode, Ann M.; Dong, Zigang; Sun, Lihua; Cao, Yang

doi:10.1038/onc.2014.32

Cited by 164 publications

(181 citation statements)

References 44 publications

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“…One of the important functions for mTORC1 is regulation of energy metabolism in cancer cells. Recent studies have shown that LMP1 promotes aerobic glycolysis in NPC cells (25,26). Aerobic glycolysis is closely correlated with a higher rate of glucose uptake, which is regulated by glucose transporters (Gluts).…”

Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-B is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-B signaling to mediate aerobic glycolysis. NF-B activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-B activation and Glut-1 transcription. Interfering NF-B signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-B signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKK␤-mediated phosphorylation of TSC2 at Ser 939 . Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-B/Glut-1 represents a novel therapeutic target against NPC.IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC pathogenesis. This study provides evidence that LMP1 upregulates Glut-1 transcription to control aerobic glycolysis and tumorigenic growth of NPC cells through mTORC1/NF-B signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-B/ Glut-1 signaling axis in the treatment of EBV-infected NPC.

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Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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“…The CNE1-LMP1 cell line, which stably expresses LMP1, was obtained from the Cancer Research Institute of Central South University (26,29). All these cells were also preserved at the Cancer Research Insitute at Xiangya School of Medicine (26,27,29,30 (30). CNE1 cells (5x10 5 cells/well) were transfected with different concentrations of pSG5-LMP1 plasmid (0, 0.5 and 1 µg/well) or with control pSG5 vector (Agilent Technologies, Inc., Santa Clara, CA, USA; 1 µg/well) using Lipofectamine 2000 (Invitrogen; Thermo Fisher Scientific, Inc.).…”

Section: Methodsmentioning

confidence: 99%

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

Liu

Tang

et al. 2017

Exp Ther Med

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Abstract. The Epstein-Barr virus (EBV) lytic cycle contributes to the development of EBV-associated diseases. EBV-encoded latent membrane protein 1 (LMP1) is key to EBV lytic replication, and our previous work indicated that epigallocatechin-3-gallate (EGCG) inhibited constitutive EBV lytic infection through the suppression of LMP1-activated phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-related protein kinase 1/2 signaling. The present study demonstrated that LMP1 in CNE-LMP1 constructed cells significantly induced the expression of the EBV lytic proteins BZLF1 (P<0.001) and BMRF1 (P<0.05) compared with CNE1 cells. Following treatment with a specific DNAzyme that targets LMP1, significantly reduced protein expression levels of BZLF1 and BMRF1 in EBV-associated epithelial carcinoma CNE1-LMP1 cells (P<0.001 and P<0.01, respectively) and lymphoma B95.8 cells (both P<0.01) were observed. Furthermore, EGCG significantly inhibited the mRNA and protein expression levels of LMP1 (P<0.05) in an apparent dose-dependent manner in CNE1-LMP1 and B95.8 cells. Thus, the present findings indicated that the molecular mechanism underlying EGCG inhibition of EBV lytic infection involves downregulation of LMP1. IntroductionEpstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the human population worldwide (1). EBV is suggested to be an environmental factor associated with the development of several human malignancies, including nasopharyngeal carcinoma (NPC), Burkitt's lymphoma, Hodgkin's disease (HD), gastric cancer, natural killer/T-cell lymphoma, acquired immune deficiency syndrome-and transplantation-associated lymphoma (2,3), breast carcinoma, and hepatocellular carcinoma (4,5). EBV, as all other herpes viruses, may establish a latent or lytic infection in host cells (6). Notably, studies suggest that EBV reactivation into a lytic cycle may contribute to the pathogenesis of malignancies (7,8). EBV lytic infection in vivo has been identified by elevated antibody titers against EBV lytic antigens and by increased viral DNA load in the serum/plasma, and these observations correspond with advanced cancer stages, poor prognosis or tumor recurrence following therapy (9,10). Additionally, serological studies have indicated that EBV lytic infection may occur months or years prior to a clinical diagnosis of NPC, HD or Burkitt's lymphoma, which suggests EBV lytic infection may be a risk factor for cancer development (11-13).Green tea contains (-)-epigallocatechin-3-gallate (EGCG), which is reported to have antioxidant, antibacterial and antitumor effects (14,15). EGCG has been indicated to modulate multiple signaling pathways, including the phosphoinositide 3-kinase (PI3-K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways, which may enable it to exert its cancer chemopreventive and therapeutic effects (16,17).EBV encoded latent membrane protein 1 (LMP1), which is considered to have oncogenic properties, has been identified in 90% of patients with NPC...

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“…LMP1 is sufficient to induce aerobic glycolysis in NPC cells (60), and GLUT1 depletion suppresses nasopharyngeal epithelial cell aerobic glycolysis, proliferation, and colony formation (62). Further studies are required to determine whether additional EBV latency proteins contribute to this phenotype.…”

Section: Lmp1 Promotes Aerobic Glycolysismentioning

confidence: 99%

Epstein-Barr Virus LMP1-Mediated Oncogenicity

Wang

Jiang

Gewurz

2017

J Virol

118

104

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Epstein-Barr virus latent membrane protein 1 (LMP1) is expressed in multiple human malignancies, including nasopharyngeal carcinoma and Hodgkin and immunosuppression-associated lymphomas. LMP1 mimics CD40 signaling to activate multiple growth and survival pathways, in particular, NF-B. LMP1 has critical roles in Epstein-Barr virus (EBV)-driven B-cell transformation, and its expression causes fatal lymphoproliferative disease in immunosuppressed mice. Here, we review recent developments in studies of LMP1 signaling, LMP1-induced host dependency factors, mouse models of LMP1 lymphomagenesis, and anti-LMP1 immunotherapy approaches.

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

Cited by 164 publications

References 44 publications

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

Epstein-Barr Virus LMP1-Mediated Oncogenicity

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