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La carboxilación reductiva apoya el crecimiento de las células tumorales con mitocondrias defectuosas
Andrew R Mullen1, William W Wheaton, Eunsook S Jin
1Department of Pediatrics, University of Texas - Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
Nature
|November 22, 2011
Resumen
Las células cancerosas con mitocondrias defectuosas utilizan la glutamina para la carboxilación reductiva, una nueva vía para generar bloques de construcción esenciales para el crecimiento tumoral. Esta adaptación metabólica apoya la síntesis de macromoléculas cuando el metabolismo oxidativo se ve afectado.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología del cáncer Biología del cáncer.
- Las vías metabólicas.
Sus antecedentes:
- El metabolismo mitocondrial suministra precursores para la síntesis de macromoléculas en las células cancerosas.
- La tumorigénesis requiere la síntesis de lípidos, apoyada por el citrato y la acetil-coenzima A del metabolismo oxidativo.
- Las mutaciones en el ciclo del ácido cítrico (CAC) o en la cadena de transporte de electrones (ETC) perjudican la función mitocondrial, dejando inciertos los mecanismos de generación de precursores.
Objetivo del estudio:
- Investigar cómo las células cancerosas con mitocondrias defectuosas generan precursores para la síntesis de macromoléculas.
- Identificar vías metabólicas alternativas que apoyen el crecimiento tumoral en ausencia de un metabolismo oxidativo funcional.
Principales métodos:
- Análisis de las vías metabólicas en las células tumorales con mutaciones en los componentes CAC o ETC.
- Investigación del metabolismo de la glutamina y la carboxilación reductiva.
- Pruebas de actividad enzimática para NADP (((+) / isocitrato deshidrogenasa dependiente de NADPH.
- Perfilado metabólico en células derivadas del paciente y células farmacológicamente inhibidas.
Principales resultados:
- Las células tumorales con mitocondrias defectuosas utilizan predominantemente la carboxilación reductora dependiente de la glutamina para la formación de citrato.
- Esta vía utiliza isoformas de isocitrato deshidrogenasa y proporciona acetil-coenzima A para la síntesis de lípidos.
- La vía reductora genera intermedios de cuatro carbonos para los metabolitos del CAC y los precursores de las macromoléculas.
- Esta adaptación metabólica es dominante en las células malignas de rápido crecimiento con mutaciones ETC o CAC.
Conclusiones:
- Una vía novedosa y versátil dependiente de la glutamina apoya el crecimiento de las células tumorales al revertir las reacciones canónicas del CAC.
- Esta vía explica la generación de precursores en las células cancerosas con un metabolismo mitocondrial alterado.
- Dirigirse a esta vía reductora podría ofrecer estrategias terapéuticas para tipos específicos de cáncer.
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