1. Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells
- Author
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Beauvarlet, Jennifer, Bensadoun, Paul, Darbo, Elodie, Labrunie, Gaelle, Rousseau, Benoît, Richard, Elodie, Draskovic, Irena, Londono-Vallejo, Arturo, Dupuy, Jean-William, Nath Das, Rabindra, Guédin, Aurore, Robert, Guillaume, Orange, Francois, Croce, Sabrina, Valesco, Valerie, Soubeyran, Pierre, Ryan, Kevin M, Mergny, Jean-Louis, Djavaheri-Mergny, Mojgan, Institut Bergonié [Bordeaux], UNICANCER, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Sorbonne Université (SU), Institut Curie [Paris], Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), University of Glasgow, Czech Academy of Sciences [Prague] (CAS), Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Conditions Extrêmes et Matériaux : Haute Température et Irradiation (CEMHTI), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Centre Commun de Mesures Imagerie Cellulaire, Université de Lille, Sciences et Technologies, Telomeres and Cancer Laboratory, Institut Curie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié - CRLCC Bordeaux, Régulation et dynamique des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
- Subjects
Male ,[SDV]Life Sciences [q-bio] ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Ataxia Telangiectasia Mutated Proteins ,Mice, SCID ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Ligands ,Mice ,Chemical Biology and Nucleic Acid Chemistry ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Mice, Inbred NOD ,Cell Line, Tumor ,Neoplasms ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Autophagy ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Animals ,Humans ,Cellular Senescence ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Xenograft Model Antitumor Assays ,G-Quadruplexes ,A549 Cells ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,DNA Damage ,HeLa Cells ,Signal Transduction - Abstract
International audience; G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.
- Published
- 2019