Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells
Open accessAbstract
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.
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Cellular treatment with G4 ligands, such as PDS or 20A, is linked to anti-tumorigenic effects and G2/M cell cycle arrest.
“One study has linked cellular treatment with G4 ligands, such as PDS or 20A, to anti-tumorigenic effects and G2/M cell cycle arrest (71).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [71]
The Discussion reports that the G4 ligand 20A inhibits cancer-cell growth in vitro and in vivo, supporting the anti-tumorigenic part of the claim. The Results describe growth arrest through senescence and apoptosis, but do not identify it as G2/M arrest; the passages found also do not establish the claimed effect for PDS (searched: G2/M, PDS/pyridostatin, and cell-cycle arrest). (LLM, conf=0.86)
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Self-citationRecent advances on G-quadruplex for biosensing, bioimaging and cancer therapy
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The Relevance of G-Quadruplexes for DNA Repair
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Major Achievements in the Design of Quadruplex-Interactive Small Molecules
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Ligands stimulating antitumour immunity as the next G-quadruplex challenge
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“The study presents the ATM/autophagy axis as a key player for cell fate between senescence and apoptosis, therefore suggesting that autophagy can be a target to induce G4 ligand-dependent cancer cell death [28].”
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UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
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ATM and p53 in aging and cancer: a double-edged sword in genomic integrity
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G-quadruplex-mediated genomic instability drives SNVs in cancer
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Self-citationRNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism
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G-quadruplex ligands as potent regulators of lysosomes
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Self-citationG-quadruplexes in MTOR and induction of autophagy
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Telomere-related DNA damage response pathways in cancer therapy: prospective targets
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Modulating gene expression in breast cancer via DNA secondary structure and the CRISPR toolbox
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Self-citationRecent Progress and Potential of G4 Ligands in Cancer Immunotherapy
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PP2C phosphatases—terminators of suicidal thoughts
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Harnessing G-quadruplex ligands for lung cancer treatment: A comprehensive overview
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Self-citationResf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer
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- Authors
- Beauvarlet, J., Bensadoun, P., Darbo, E., Labrunie, G., Rousseau, B., Richard, E., Draskovic, I., Londono-Vallejo, A., Dupuy, J.-W., Nath Das, R., Guédin, A., Robert, G., Orange, F., Croce, S., Valesco, V., Soubeyran, P., Ryan, K. M., Mergny, J.-L., & Djavaheri-Mergny, M.
- Affiliations
- Université de Bordeaux (FR)
- Institut Bergonié, Université de Bordeaux, INSERM U1218, F-33076 Bordeaux, France
- Service commun des animaleries, Université de Bordeaux, F-33000 Bordeaux, France
- Institut Curie, PSL Research University, CNRS, UMR3244, F-75005 Paris, France
- ARNA Laboratory, Université de Bordeaux, INSERM U1212, CNRS UMR 5320, IECB, F-33600, Pessac, France
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Côte d’Azur, Centre Commun de Microscopie Appliquée (CCMA), 06108 Nice, France
- Institut Bergonié (FR)
- Department of Biopathology, Institut Bergonié, F-33076 Bordeaux, France
- Cancer Research UK Scotland Institute (GB)
- Corresponding author
- Mergny, Jean-Louis
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-02-13
- Volume
- 47
- Issue
- 6
- Pages
- 2739-2756
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC6451122
- OpenAlex
- W2913579109
- Cited by
- 73
- References
- 80
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 11 · 2023: 6 · 2022: 8 · 2021: 20 · 2020: 13 · 2019: 4
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- SYMBIT project (CZ.02.1.01/0.0/0.0/15_003/0000477)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- G-quadruplex ligands, ATM, autophagy, cellular senescence, apoptosis, cancer cells, growth arrest, DNA damage response, lysosomal pathway, Chk1 activation, ATG5, ATG7, anticancer drug synergy
- MeSH terms
- A549 Cells, Animals, Autophagy, DNA Damage, HeLa Cells, Humans, Ligands, Male, Neoplasms, Signal Transduction, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, Apoptosis, Mice, Knockout, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, G-Quadruplexes, Ataxia Telangiectasia Mutated Proteins
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