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A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment

Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival...

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Autores principales: Boumya, Sara, Fallarini, Silvia, Siragusa, Sonia, Petrarolo, Giovanni, Aprile, Silvio, Audrito, Valentina, La Motta, Concettina, Garavaglia, Silvia, Moro, Laura, Pinton, Giulia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094992/
https://www.ncbi.nlm.nih.gov/pubmed/37047661
http://dx.doi.org/10.3390/ijms24076689
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author Boumya, Sara
Fallarini, Silvia
Siragusa, Sonia
Petrarolo, Giovanni
Aprile, Silvio
Audrito, Valentina
La Motta, Concettina
Garavaglia, Silvia
Moro, Laura
Pinton, Giulia
author_facet Boumya, Sara
Fallarini, Silvia
Siragusa, Sonia
Petrarolo, Giovanni
Aprile, Silvio
Audrito, Valentina
La Motta, Concettina
Garavaglia, Silvia
Moro, Laura
Pinton, Giulia
author_sort Boumya, Sara
collection PubMed
description Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.
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spelling pubmed-100949922023-04-13 A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment Boumya, Sara Fallarini, Silvia Siragusa, Sonia Petrarolo, Giovanni Aprile, Silvio Audrito, Valentina La Motta, Concettina Garavaglia, Silvia Moro, Laura Pinton, Giulia Int J Mol Sci Article Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer. MDPI 2023-04-03 /pmc/articles/PMC10094992/ /pubmed/37047661 http://dx.doi.org/10.3390/ijms24076689 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Boumya, Sara
Fallarini, Silvia
Siragusa, Sonia
Petrarolo, Giovanni
Aprile, Silvio
Audrito, Valentina
La Motta, Concettina
Garavaglia, Silvia
Moro, Laura
Pinton, Giulia
A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title_full A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title_fullStr A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title_full_unstemmed A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title_short A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment
title_sort selective aldh1a3 inhibitor impairs mesothelioma 3-d multicellular spheroid growth and neutrophil recruitment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094992/
https://www.ncbi.nlm.nih.gov/pubmed/37047661
http://dx.doi.org/10.3390/ijms24076689
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