Zhang Jun, Jia Lin, Lin Weitao, Yip Yim Ling, Lo Kwok Wai, Lau Victoria Ming Yi, Zhu Dandan, Tsang Chi Man, Zhou Yuan, Deng Wen, Lung Hong Lok, Lung Maria Li, Cheung Lai Man, Tsao Sai Wah
School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
J Virol. 2017 Feb 28;91(6). doi: 10.1128/JVI.02168-16. Print 2017 Mar 15.
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 Ser 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. 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-κB signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-κB/Glut-1 signaling axis in the treatment of EBV-infected NPC.
越来越多的证据表明，致癌病毒蛋白在肿瘤发生过程中激活有氧糖酵解方面发挥着关键作用，但其潜在机制在很大程度上尚不清楚。爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）是一种具有强大细胞信号传导特性的跨膜蛋白，具有致瘤转化特性。NF-κB的激活是介导LMP1许多下游转化特性的主要信号通路。在此我们报告，LMP1对mTORC1的激活是激活NF-κB信号以介导有氧糖酵解的关键调节因子。NF-κB的激活参与了LMP1诱导的葡萄糖转运蛋白1（Glut-1）转录上调和鼻咽癌（NPC）细胞的生长。阻断mTORC1信号的活性有效地抑制了LMP1诱导的NF-κB激活和Glut-1转录。干扰NF-κB信号对mTORC1活性没有影响，但有效地改变了Glut-1转录。Glut-1的荧光素酶启动子分析也证实Glut-1基因是NF-κB信号的直接靶基因。此外，我们证明LMP1的C末端激活区域2（CTAR2）是参与mTORC1激活的关键结构域，主要通过IKKβ介导的TSC2在Ser处的磷酸化。Glut-1的缺失有效地导致有氧糖酵解的抑制、细胞增殖的抑制、集落形成以及表达LMP1的鼻咽上皮（NPE）细胞致瘤生长特性的减弱。这些发现表明，靶向mTORC1/NF-κB/Glut-1信号轴是针对NPC的一种新型治疗靶点。有氧糖酵解是包括NPC在内的癌症的特征之一。最近的研究表明LMP1在介导有氧糖酵解中起作用。LMP1表达在NPC中很常见。LMP1在有氧糖酵解中诱导的重要信号通路的阐明有助于理解NPC的发病机制。这项研究提供了证据，表明LMP1通过mTORC1/NF-κB信号上调Glut-1转录以控制NPC细胞的有氧糖酵解和致瘤生长。我们的结果揭示了在治疗EBV感染的NPC中针对mTORC1/NF-κB/Glut-1信号轴的新型治疗靶点。
