title: AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest.
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.
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Elena
authors: E
authors: Doménech
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Carolina
authors: C
authors: Maestre
authors: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors: Lorena
authors: L
authors: Esteban-Martínez
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: David
authors: D
authors: Partida
authors: ICREA and Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain.
authors: Rosa
authors: R
authors: Pascual
authors: ICREA and Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain.
authors: Gonzalo
authors: G
authors: Fernández-Miranda
authors: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors: Esther
authors: E
authors: Seco
authors: Spectroscopy and Nuclear Magnetic Resonance Unit, CNIO, Madrid 28029, Spain.
authors: Ramón
authors: R
authors: Campos-Olivas
authors: Confocal Microscopy Unit, CNIO, Madrid  28029, Spain.
authors: Manuel
authors: M
authors: Pérez
authors: Confocal Microscopy Unit, CNIO, Madrid  28029, Spain.
authors: Diego
authors: D
authors: Megias
authors: Division of Endocrinology, Diabetes & Nutrition, Boston University School of Medicine, Boston, Massachusetts 02215, USA.
authors: Katherine
authors: K
authors: Allen
authors: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
authors: Miguel
authors: M
authors: López
authors: Division of Endocrinology, Diabetes & Nutrition, Boston University School of Medicine, Boston, Massachusetts 02215, USA.
authors: Asish K
authors: AK
authors: Saha
authors: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
authors: Guillermo
authors: G
authors: Velasco
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors: Eduardo
authors: E
authors: Rial
authors: ICREA and Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain.
authors: Raúl
authors: R
authors: Méndez
authors: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors: Patricia
authors: P
authors: Boya
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: María
authors: M
authors: Salazar-Roa
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Marcos
authors: M
authors: Malumbres
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000648:ultrastructure; D006019:Glycolysis; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D061986:MCF-7 Cells; D018345:Mice, Knockout; D008819:Mice, Nude; D018613:Microscopy, Confocal; D017239:Paclitaxel / Q000494:pharmacology; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; C107345:PFKFB3 protein, human; C000595376:PFKFB3 protein, mouse; D025481:Phosphofructokinase-2; D055372:AMP-Activated Protein Kinases; D017239:Paclitaxel