Epstein-Barr virus-encoded latent membrane protein 1 upregulates glucose transporter 1 transcription via the mTORC1/NF-κB signaling pathways

Jun Zhang, Lin Jia, Weitao Lin, Yim Ling Yip, Kwok Wai Lo, Victoria Ming Yi Lau, Dandan Zhu, Chi Man Tsang, Yuan Zhou, Wen Deng, Hong Lok LUNG, Maria Li Lung, Lai Man Cheung, Sai Wah Tsao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

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-κB 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-κB signaling to mediate aerobic glycolysis. NF-κB 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-κB activation and Glut-1 transcription. Interfering NF-κB 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-κB signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKKβ-mediated phosphorylation of TSC2 at Ser939. 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-κB/Glut-1 represents a novel therapeutic target against NPC.

Original languageEnglish
Article numbere02168-16
JournalJournal of Virology
Volume91
Issue number6
DOIs
Publication statusPublished - 2017

Scopus Subject Areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

User-Defined Keywords

  • Glut-1
  • LMP1
  • MTORC1
  • Nasopharyngeal carcinoma
  • NF-κB
  • NF-κB

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