Undifferentiated nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) latent infection. The EBV-encoded latent membrane protein 1 (LMP1) oncogene is believed to be important in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways to induce proliferation, transformation, angiogenesis and invasiveness as well as modulation of energy metabolism. In this study, we report that LMP1 increases cell uptake of glucose and glutamine, enhances LDHA activity and lactate production, but reduces pyruvate kinase activity and pyruvate concentration. LMP1 also increases the phosphorylation of PKM2, LDHA and FGFR1 as well as expression of PDHK1, FGFR1, c-Myc and HIF-1α regardless of oxygen availability. This suggests that LMP1 promotes aerobic glycolysis. In addition to FGFR1, LMP1 also upregulates FGF2, the FGFR1 ligand, setting up a constitutive activation loop of FGFR1 signaling to promote aerobic glycolysis. FGFR1 inhibitors also abolish LMP1-mediated cellular transformation (proliferation and anchorage-independent growth) as well as cell migration and invasion in nasopharyngeal epithelial cells. Immunohistochemical staining revealed that a high level of phosphorylated FGFR1 is common in primary NPC specimens, and that this correlated with the expression of LMP1. Inhibition of FGFR1 activity in NPC cells results in the suppression of cell proliferation and anchorage-independent growth. Our current findings demonstrate that LMP1-mediated FGFR1 activation contributes to growth and transformation of epithelial cells, thereby implicating FGF2/FGFR1 signaling activation in the EBV-driven pathogenesis of NPC.

Citation Format: Kwok Fung Lo, Christopher W Dawson, Lawrence S Young, Kwok Wai Lo. Activation of the FGFR1 signaling pathway by the epstein-barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-093. doi:10.1158/1538-7445.AM2015-LB-093