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IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage

Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and p...

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Autores principales: Panneerselvam, Janani, Srivastava, Akhil, Mehta, Meghna, Chen, Allshine, Zhao, Yan D., Munshi, Anupama, Ramesh, Rajagopal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966580/
https://www.ncbi.nlm.nih.gov/pubmed/31783569
http://dx.doi.org/10.3390/cancers11121879
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author Panneerselvam, Janani
Srivastava, Akhil
Mehta, Meghna
Chen, Allshine
Zhao, Yan D.
Munshi, Anupama
Ramesh, Rajagopal
author_facet Panneerselvam, Janani
Srivastava, Akhil
Mehta, Meghna
Chen, Allshine
Zhao, Yan D.
Munshi, Anupama
Ramesh, Rajagopal
author_sort Panneerselvam, Janani
collection PubMed
description Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and protein expression of GLI1 in lung tumor cells, but not in normal cells. GLI1 reporter assay and mRNA studies demonstrated that IL-24 regulates GLI1 at the post-transcriptional level by favoring mRNA degradation. Associated with GLI1 inhibition was marked suppression of the ATM-mediated DDR pathway resulting in increased DNA damage, as evidenced by γ-H2AX foci and Comet assay. Furthermore, attenuation of GLI1-associated DDR by IL-24 increased caspase-3 and PARP activity, resulting in cancer cell apoptosis. GLI1 inhibition and overexpression confirmed that IL-24-mediated anti-tumor effects involved the GLI-dependent pathway. Finally, we observed that IL-24-mediated alteration in GLI1 is independent of the canonical hedgehog-signaling pathway. Our study provides evidence that IL-24 treatment induces DNA damage, and reduces GLI1 expression and offers an opportunity for testing IL-24-based therapy for inhibiting GLI1 in lung cancer.
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spelling pubmed-69665802020-02-04 IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage Panneerselvam, Janani Srivastava, Akhil Mehta, Meghna Chen, Allshine Zhao, Yan D. Munshi, Anupama Ramesh, Rajagopal Cancers (Basel) Article Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and protein expression of GLI1 in lung tumor cells, but not in normal cells. GLI1 reporter assay and mRNA studies demonstrated that IL-24 regulates GLI1 at the post-transcriptional level by favoring mRNA degradation. Associated with GLI1 inhibition was marked suppression of the ATM-mediated DDR pathway resulting in increased DNA damage, as evidenced by γ-H2AX foci and Comet assay. Furthermore, attenuation of GLI1-associated DDR by IL-24 increased caspase-3 and PARP activity, resulting in cancer cell apoptosis. GLI1 inhibition and overexpression confirmed that IL-24-mediated anti-tumor effects involved the GLI-dependent pathway. Finally, we observed that IL-24-mediated alteration in GLI1 is independent of the canonical hedgehog-signaling pathway. Our study provides evidence that IL-24 treatment induces DNA damage, and reduces GLI1 expression and offers an opportunity for testing IL-24-based therapy for inhibiting GLI1 in lung cancer. MDPI 2019-11-27 /pmc/articles/PMC6966580/ /pubmed/31783569 http://dx.doi.org/10.3390/cancers11121879 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Panneerselvam, Janani
Srivastava, Akhil
Mehta, Meghna
Chen, Allshine
Zhao, Yan D.
Munshi, Anupama
Ramesh, Rajagopal
IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title_full IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title_fullStr IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title_full_unstemmed IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title_short IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage
title_sort il-24 inhibits lung cancer growth by suppressing gli1 and inducing dna damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966580/
https://www.ncbi.nlm.nih.gov/pubmed/31783569
http://dx.doi.org/10.3390/cancers11121879
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