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Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma
BACKGROUND: The successful targeting of neuroblastoma (NB) by associating tumor-initiating cells (TICs) is a major challenge in the development of new therapeutic strategies. The subfamily of aldehyde dehydrogenases 1 (ALDH1) isoenzymes, which comprises ALDH1A1, ALDH1A2, and ALDH1A3, is involved in...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057398/ https://www.ncbi.nlm.nih.gov/pubmed/27724856 http://dx.doi.org/10.1186/s12885-016-2820-1 |
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author | Flahaut, Marjorie Jauquier, Nicolas Chevalier, Nadja Nardou, Katya Balmas Bourloud, Katia Joseph, Jean-Marc Barras, David Widmann, Christian Gross, Nicole Renella, Raffaele Mühlethaler-Mottet, Annick |
author_facet | Flahaut, Marjorie Jauquier, Nicolas Chevalier, Nadja Nardou, Katya Balmas Bourloud, Katia Joseph, Jean-Marc Barras, David Widmann, Christian Gross, Nicole Renella, Raffaele Mühlethaler-Mottet, Annick |
author_sort | Flahaut, Marjorie |
collection | PubMed |
description | BACKGROUND: The successful targeting of neuroblastoma (NB) by associating tumor-initiating cells (TICs) is a major challenge in the development of new therapeutic strategies. The subfamily of aldehyde dehydrogenases 1 (ALDH1) isoenzymes, which comprises ALDH1A1, ALDH1A2, and ALDH1A3, is involved in the synthesis of retinoic acid, and has been identified as functional stem cell markers in diverse cancers. By combining serial neurosphere passages with gene expression profiling, we have previously identified ALDH1A2 and ALDH1A3 as potential NB TICs markers in patient-derived xenograft tumors. In this study, we explored the involvement of ALDH1 isoenzymes and the related ALDH activity in NB aggressive properties. METHODS: ALDH activity and ALDH1A1/A2/A3 expression levels were measured using the ALDEFLUOR™ kit, and by real-time PCR, respectively. ALDH activity was inhibited using the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB), and ALDH1A3 gene knock-out was generated through the CRISPR/Cas9 technology. RESULTS: We first confirmed the enrichment of ALDH1A2 and ALDH1A3 mRNA expression in NB cell lines and patient-derived xenograft tumors during neurosphere passages. We found that high ALDH1A1 expression was associated with less aggressive NB tumors and cell lines, and correlated with favorable prognostic factors. In contrast, we observed that ALDH1A3 was more widely expressed in NB cell lines and was associated with poor survival and high-risk prognostic factors. We also identified an important ALDH activity in various NB cell lines and patient-derived xenograft tumors. Specific inhibition of ALDH activity with diethylaminobenzaldehyde (DEAB) resulted in a strong reduction of NB cell clonogenicity, and TIC self-renewal potential, and partially enhanced NB cells sensitivity to 4-hydroxycyclophosphamide. Finally, the specific knock-out of ALDH1A3 via CRISPR/Cas9 gene editing reduced NB cell clonogenicity, and mediated a cell type-dependent inhibition of TIC self-renewal properties. CONCLUSIONS: Together our data uncover the participation of ALDH enzymatic activity in the aggressive properties and 4-hydroxycyclophosphamide resistance of NB, and show that the specific ALDH1A3 isoenzyme increases the aggressive capacities of a subset of NB cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2820-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5057398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-50573982016-10-20 Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma Flahaut, Marjorie Jauquier, Nicolas Chevalier, Nadja Nardou, Katya Balmas Bourloud, Katia Joseph, Jean-Marc Barras, David Widmann, Christian Gross, Nicole Renella, Raffaele Mühlethaler-Mottet, Annick BMC Cancer Research Article BACKGROUND: The successful targeting of neuroblastoma (NB) by associating tumor-initiating cells (TICs) is a major challenge in the development of new therapeutic strategies. The subfamily of aldehyde dehydrogenases 1 (ALDH1) isoenzymes, which comprises ALDH1A1, ALDH1A2, and ALDH1A3, is involved in the synthesis of retinoic acid, and has been identified as functional stem cell markers in diverse cancers. By combining serial neurosphere passages with gene expression profiling, we have previously identified ALDH1A2 and ALDH1A3 as potential NB TICs markers in patient-derived xenograft tumors. In this study, we explored the involvement of ALDH1 isoenzymes and the related ALDH activity in NB aggressive properties. METHODS: ALDH activity and ALDH1A1/A2/A3 expression levels were measured using the ALDEFLUOR™ kit, and by real-time PCR, respectively. ALDH activity was inhibited using the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB), and ALDH1A3 gene knock-out was generated through the CRISPR/Cas9 technology. RESULTS: We first confirmed the enrichment of ALDH1A2 and ALDH1A3 mRNA expression in NB cell lines and patient-derived xenograft tumors during neurosphere passages. We found that high ALDH1A1 expression was associated with less aggressive NB tumors and cell lines, and correlated with favorable prognostic factors. In contrast, we observed that ALDH1A3 was more widely expressed in NB cell lines and was associated with poor survival and high-risk prognostic factors. We also identified an important ALDH activity in various NB cell lines and patient-derived xenograft tumors. Specific inhibition of ALDH activity with diethylaminobenzaldehyde (DEAB) resulted in a strong reduction of NB cell clonogenicity, and TIC self-renewal potential, and partially enhanced NB cells sensitivity to 4-hydroxycyclophosphamide. Finally, the specific knock-out of ALDH1A3 via CRISPR/Cas9 gene editing reduced NB cell clonogenicity, and mediated a cell type-dependent inhibition of TIC self-renewal properties. CONCLUSIONS: Together our data uncover the participation of ALDH enzymatic activity in the aggressive properties and 4-hydroxycyclophosphamide resistance of NB, and show that the specific ALDH1A3 isoenzyme increases the aggressive capacities of a subset of NB cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2820-1) contains supplementary material, which is available to authorized users. BioMed Central 2016-10-10 /pmc/articles/PMC5057398/ /pubmed/27724856 http://dx.doi.org/10.1186/s12885-016-2820-1 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Flahaut, Marjorie Jauquier, Nicolas Chevalier, Nadja Nardou, Katya Balmas Bourloud, Katia Joseph, Jean-Marc Barras, David Widmann, Christian Gross, Nicole Renella, Raffaele Mühlethaler-Mottet, Annick Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title | Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title_full | Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title_fullStr | Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title_full_unstemmed | Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title_short | Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma |
title_sort | aldehyde dehydrogenase activity plays a key role in the aggressive phenotype of neuroblastoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057398/ https://www.ncbi.nlm.nih.gov/pubmed/27724856 http://dx.doi.org/10.1186/s12885-016-2820-1 |
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