Journal
LEUKEMIA
Volume 29, Issue 5, Pages 1163-1176Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.324
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Funding
- Fondation ARC (Association pour la Recherche sur le Cancer)
- Agence Nationale de la Recherche [ANR-09-JCJC-0003, LABEX SIGNALIFE ANR-11-LABX-0028-01]
- Fondation de France
- Centre Scientifique de Monaco
- Canceropole PACA
- Fondation ARC and by la Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- la Ville de Nice
- Agence Nationale de la Recherche (ANR) [ANR-09-JCJC-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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