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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology
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Autophagy / genetics
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Autophagy / physiology*
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Blotting, Western
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Cdc20 Proteins / genetics
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Cdc20 Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Cells, Cultured
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Female
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Fibroblasts / metabolism*
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Fibroblasts / ultrastructure
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Glycolysis*
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Humans
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M Phase Cell Cycle Checkpoints / genetics
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M Phase Cell Cycle Checkpoints / physiology*
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MCF-7 Cells
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Mice, Knockout
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Mice, Nude
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Microscopy, Confocal
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Paclitaxel / pharmacology
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Phosphofructokinase-2 / genetics
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Phosphofructokinase-2 / metabolism*
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RNA Interference
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cdc20 Proteins
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Cdc20 protein, mouse
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PFKFB3 protein, human
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PFKFB3 protein, mouse
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Phosphofructokinase-2
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AMP-Activated Protein Kinases
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Paclitaxel