GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-kappa B (NF-kappa B) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1 alpha (HIF-1 alpha). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1 alpha, vegf-alpha, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-kappa B-dependent induction of HIF-1 alpha and has a key role in lymphoma vascularization and aggressiveness.