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

• Published in: Leukemia Vol. 29; no. 5; pp. 1163 - 1176
• Main Authors: Chiche, J, Pommier, S, Beneteau, M, Mondragón, L, Meynet, O, Zunino, B, Mouchotte, A, Verhoeyen, E, Guyot, M, Pagès, G, Mounier, N, Imbert, V, Colosetti, P, Goncalvès, D, Marchetti, S, Brière, J, Carles, M, Thieblemont, C, Ricci, J-E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2015; Nature Publishing Group
• Subjects: 13/51; 631/67/1990/291/1621/1915; 631/67/70; 64; 64/60; 82; 82/80; 96; Analysis; Animals; Biopsy; Cancer; Cancer Research; Care and treatment; Cell Line, Tumor; Critical Care Medicine; Deregulation; Diagnosis; Enzyme Inhibitors - chemistry; Enzymes; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) - metabolism; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; HeLa Cells; Hematology; Hodgkin's disease; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Intensive; Internal Medicine; Lymphocytes B; Lymphoma; Lymphoma - metabolism; Lymphoma, Non-Hodgkin - metabolism; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Mutants; NF-kappa B p50 Subunit - metabolism; NF-κB protein; Non-Hodgkin's lymphoma; Oncology; original-article; Phenotype; Proto-Oncogene Proteins c-myc - metabolism; TNF Receptor-Associated Factor 2 - metabolism; TRAF2 protein; Transcription; Transformed cells; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascularization; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.324

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-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). 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
α
, vegf-a
,
nfkbia
mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.