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G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structure...

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Autores principales: Miglietta, Giulia, Russo, Marco, Duardo, Renée C, Capranico, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266585/
https://www.ncbi.nlm.nih.gov/pubmed/34139015
http://dx.doi.org/10.1093/nar/gkab500
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author Miglietta, Giulia
Russo, Marco
Duardo, Renée C
Capranico, Giovanni
author_facet Miglietta, Giulia
Russo, Marco
Duardo, Renée C
Capranico, Giovanni
author_sort Miglietta, Giulia
collection PubMed
description G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations. The studied G4 binders (pyridostatin and PhenDC3) can induce an increase of micronuclei triggering the activation of the cytoplasmic STING (stimulator of interferon response cGAMP interactor 1) signaling pathway in human and murine cancer cells. Ligand activity can then lead to type I interferon production and innate immune gene activation. Moreover, specific gene expression patterns mediated by a G4 binder in cancer cells correlate with immunological hot features and better survival in human TCGA (The Cancer Genome Atlas) breast tumors. The findings open to the development of cytostatic G4 binders as effective immunomodulators for combination immunotherapies in unresponsive tumors.
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spelling pubmed-82665852021-07-09 G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells Miglietta, Giulia Russo, Marco Duardo, Renée C Capranico, Giovanni Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations. The studied G4 binders (pyridostatin and PhenDC3) can induce an increase of micronuclei triggering the activation of the cytoplasmic STING (stimulator of interferon response cGAMP interactor 1) signaling pathway in human and murine cancer cells. Ligand activity can then lead to type I interferon production and innate immune gene activation. Moreover, specific gene expression patterns mediated by a G4 binder in cancer cells correlate with immunological hot features and better survival in human TCGA (The Cancer Genome Atlas) breast tumors. The findings open to the development of cytostatic G4 binders as effective immunomodulators for combination immunotherapies in unresponsive tumors. Oxford University Press 2021-06-17 /pmc/articles/PMC8266585/ /pubmed/34139015 http://dx.doi.org/10.1093/nar/gkab500 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemical Biology and Nucleic Acid Chemistry
Miglietta, Giulia
Russo, Marco
Duardo, Renée C
Capranico, Giovanni
G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title_full G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title_fullStr G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title_full_unstemmed G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title_short G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
title_sort g-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
topic Chemical Biology and Nucleic Acid Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266585/
https://www.ncbi.nlm.nih.gov/pubmed/34139015
http://dx.doi.org/10.1093/nar/gkab500
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