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Nucleic Acids Res. 2019 Feb 13. doi: 10.1093/nar/gkz095. [Epub ahead of print]

Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells.

Author information

1
Institut Bergonié, Université de Bordeaux, INSERM U1218, F-33076 Bordeaux, France.
2
Centre de Bioinformatique de Bordeaux, université de Bordeaux, F-33000 Bordeaux France.
3
ARNA Laboratory, Université de Bordeaux, INSERM U1212, CNRS UMR 5320, IECB, F-33600, Pessac, France.
4
Service commun des animaleries, Université de Bordeaux, F-33000 Bordeaux, France.
5
Institut Curie, PSL Research University, CNRS, UMR3244, F-75005 Paris, France.
6
Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, F-75005 Paris, France.
7
Université de Bordeaux, Centre de Génomique Fonctionnelle, Plateforme Protéome, F-33000, Bordeaux, France.
8
Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Université Côte d'Azur, F-06204 Nice, France.
9
Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), 06108 Nice, France.
10
Department of Biopathology, Institut Bergonié, F-33076 Bordeaux, France.
11
Cancer Research UK Beatson Institute, Glasgow, G611BD, UK and Institute of Cancer Sciences, University of Glasgow,Glasgow G61 1QH, UK.
12
Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65 Brno, Czech Republic.

Abstract

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.

PMID:
30759257
DOI:
10.1093/nar/gkz095

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