HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation
Hypoxia-inducible factor-1a (HIF1a) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1a acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedl...
| Autores: | , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/755080 |
| Acceso en línea: | https://hdl.handle.net/10486/755080 https://dx.doi.org/10.1016/j.celrep.2024.114103 |
| Access Level: | acceso abierto |
| Palabra clave: | HIF1α glycolysis oxygen renal cell carcinoma mitochondria NADH hypoxia tumor Medicina |
| Sumario: | Hypoxia-inducible factor-1a (HIF1a) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1a acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1a suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1a-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADHsensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this antiglycolytic function provides a molecular basis to explain how HIF1a can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio |
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