IKKβ and NF-κB Transcription Govern Lymphoma Cell Survival through AKT-Induced Plasma Membrane Trafficking of GLUT1

Abstract

All cancer cells require increased nutrient uptake to support proliferation. Here we investigated the signals that govern glucose uptake in B-cell lymphomas and determined that the protein kinase IKKβ induced GLUT1 membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKβ induced AKT activity, while IKKβ-driven NFκB transcription was required for GLUT1 surface localization downstream of AKT. Activated NFκB promoted AKT-mediated phosphorylation of the GLUT1 regulator, AKT Substrate 160kD (AS160), but was not required for AKT phosphorylation of the mammalian target of rapamycin (mTOR) regulator Tuberous Sclerosis 2 (TSC2). In Epstein Barr virus (EBV) transformed B-cells, NFκB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NFκB inhibition, an alternate carbon source ameliorated both autophagy and cell death, whereas autophagy inhibitors specifically accelerated cell death. Taken together, the results suggest that NFκB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import.

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

“…The involvement of LMP1 in aerobic glycolysis was reported in recent studies involving activation of the FGFR1 signaling pathway and c-Myc-mediated HK2 expression (25,26). LMP1 also upregulates IKK␤/NF-B signaling to modulate AKT-induced plasma membrane trafficking of Glut-1 in B cell lymphoma (14). Translocation of Glut-1 to the cell membrane by LMP1 was also observed in a recent study with immortalized nasopharyngeal epithelial cells (NP69) stably expressing LMP1 (25).…”

“…In this study, LMP1 could also directly upregulate Glut-1 transcription to drive aerobic glycolysis in multiple immortalized nasopharyngeal epithelial cell lines and the cancer cell line HONE1 via mTORC1 activation and NF-B signaling. Interestingly, upregulation of Glut-1 expression by LMP1 was not observed in B cell lymphoma in an earlier study (14). The reasons for this apparent discrepancy are unclear at this stage.…”

“…The role of LMP1 activation of NF-B signaling in regulating activity of Glut-1 has been reported for B cell lymphomas (14). Its involvement in nasopharyngeal carcinoma is unclear.…”

Epstein-Barr Virus LMP1-Mediated Oncogenicity

“…LMP1 acts as a metabolism master regulator in lymphoblastoid and nasopharyngeal carcinoma (NPC) cells by promoting aerobic glycolysis, the so-called Warburg effect that supplies transformed cells with ATP and anabolic building blocks (58). In a pioneering study, LMP1-mediated NF-B and AKT/PI3K pathways were found to enhance the transcription and plasma membrane translocation of glucose transporter 1 (GLUT1) (58).…”

“…In a pioneering study, LMP1-mediated NF-B and AKT/PI3K pathways were found to enhance the transcription and plasma membrane translocation of glucose transporter 1 (GLUT1) (58). LMP1 signaling also increases the GLUT1 half-life to further upregulate GLUT1 (59) and also enhances glycolytic flux by upregulating the first glycolysis pathway enzyme, hexokinase 2 (60).…”