Reference

largecoverNat Cell Biol. 2015 Aug 31. doi: 10.1038/ncb3231

Authors

Elena Doménech, Carolina Maestre, Lorena Esteban-Martínez, David Partida, Rosa Pascual, Gonzalo Fernández-Miranda, Esther Seco, Ramón Campos-Olivas, Manuel Pérez, Diego Megias, Katherine Allen, Miguel López, Asish K. Saha, Guillermo Velasco, Eduardo Rial, Raúl Méndez, Patricia Boya, María Salazar-Roa & Marcos Malumbres

Abstract

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

Description

Cómo las células generan la energía necesaria para el ciclo de división celular no se conoce todavía en detalle. Uno de los procesos que probablemente consumen más energía es el proceso de la segregación cromosomal, debido entre otras cosas al ATP necesario para mantener la dinámica de los microtúbulos en el huso mitótico. En el trabajo de Doménech et al. los autores describen que la parada mitótica, como la originada por venenos de microtubulos (taxol, etc.) genera un déficit de energía en parte debido a la eliminación de las mitocondrias por autofagia. En esas condiciones, una ruta molecular en la que intervienen AMPK y PFKFB3 induce la glucólisis y las células paradas en mitosis muestran unos requerimientos aumentados a la glucosa, una adición que puede tener implicaciones en terapia del cáncer.

 

CDC group CNIO

 

REFERENCIA DEL GRUPO INVESTIGADOR

 

El grupo de División Celular y Cáncer del CNIO está interesado en los mecanismos de control del ciclo de división celular en células de mamíferos y su desregulación en cáncer. Entre los reguladores mitóticos, el grupo se ha concentrado en el estudio de quinasas y fosfatasas debido a su potencial terapéutico, así como en otros procesos de relevancia como la degradación de proteínas por proteólisis o los puntos de control (checkpoints) que controlan la progresión por las distintas fases del ciclo celular. El uso de modelos animales con mutaciones en genes específicos ha permitido el estudio de la relevancia fisiológica de muchos de esos reguladores en diversos tejidos, así como su potencial terapéutico en modelos de desarrollo tumoral.

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