AMPK regula la homeostasis de NADPH para promover la supervivencia de las células tumorales durante el estrés
Sang-Min Jeon1, Navdeep S Chandel, Nissim Hay
1Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Nature
|June 5, 2012
Resumen
La activación de AMPK ayuda a las células cancerosas a sobrevivir al estrés metabólico mediante la regulación de los niveles de NADPH. Esta vía es crucial para el crecimiento tumoral y la supervivencia en condiciones de energía limitada.
Área de la Ciencia:
- Biología celular Biología celular.
- Regulación del metabolismo La regulación del metabolismo
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- El estrés metabólico es vital para el crecimiento de tumores sólidos, pero los mecanismos de muerte celular y supervivencia no están claros.
- La vía de la proteína quinasa B1 (LKB1) del hígado activada por AMP (AMPK) es clave en la adaptación metabólica.
- Las células deficientes en LKB1 o AMPK muestran resistencia a la transformación oncogénica y a la tumorigénesis.
Objetivo del estudio:
- Para dilucidar los mecanismos por los cuales AMPK promueve la adaptación metabólica en las células tumorales.
- Investigar el papel de la AMPK en la supervivencia celular bajo estrés metabólico.
- Para entender la función de AMPK en el mantenimiento de NADPH para la supervivencia de las células cancerosas.
Principales métodos:
- Investigó la activación de AMPK durante el estrés energético.
- Se analizaron las vías de generación y consumo de NADPH.
- Examinó el papel de las carboxilasas acetil-CoA (ACC1 y ACC2) en los efectos mediados por AMPK.
- Utilizó experimentos de activación y eliminación de genes.
- Se evaluó el crecimiento independiente del anclaje y la formación de tumores sólidos in vivo.
Principales resultados:
- La activación de AMPK prolonga la supervivencia celular a través de la regulación redox bajo estrés energético.
- La AMPK induce rutas alternativas para mantener el NADPH cuando la vía del fosfato de pentosa está deteriorada.
- AMPK inhibe ACC1 y ACC2, disminuyendo el consumo de NADPH y aumentando su generación.
- La eliminación de ACC1 / ACC2 imita la activación de AMPK, promoviendo el crecimiento tumoral.
- La activación del ACC1/ACC2 atenúa el crecimiento tumoral.
Conclusiones:
- La AMPK es crítica para la supervivencia de las células cancerosas bajo estrés energético al mantener los niveles de NADPH.
- El papel de AMPK se extiende más allá de la homeostasis de ATP para incluir el mantenimiento esencial de NADPH.
- Dirigirse a la vía AMPK-ACC podría ofrecer estrategias terapéuticas para el cáncer.
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