Titre

Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma.

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Flahaut, M.
Auteure/Auteur
Jauquier, N.
Auteure/Auteur
Chevalier, N.
Auteure/Auteur
Nardou, K.
Auteure/Auteur
Balmas Bourloud, K.
Auteure/Auteur
Joseph, J.M.
Auteure/Auteur
Barras, D.
Auteure/Auteur
Widmann, C.
Auteure/Auteur
Gross, N.
Auteure/Auteur
Renella, R.
Auteure/Auteur
Mühlethaler-Mottet, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1471-2407
Statut éditorial
Publié
Date de publication
2016
Volume
16
Numéro
1
Première page
781
Peer-reviewed
Oui
Langue
anglais
Résumé
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.
PID Serval
serval:BIB_8AFB2FAA16EB
DOI
PMID
Permalien
Open Access
Oui
Date de création
2016-10-19T10:55:48.696Z
Date de création dans IRIS
2025-05-21T02:40:45Z
Fichier(s)
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BIB_8AFB2FAA16EB.P001.pdf

Version du manuscrit

published

Licence

https://creativecommons.org/licenses/by/4.0

Taille

2.25 MB

Format

Adobe PDF

PID Serval

serval:BIB_8AFB2FAA16EB.P001

URN

urn:nbn:ch:serval-BIB_8AFB2FAA16EB0

Somme de contrôle

(MD5):97e9870c7ebe94d58c2b5831a4d12d5f

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Nom

BMC Cancer Additional Files.pdf

Version du manuscrit

supplementary

Licence

https://creativecommons.org/licenses/by/4.0

Taille

2.37 MB

Format

Adobe PDF

PID Serval

serval:BIB_8AFB2FAA16EB.S002

Somme de contrôle

(MD5):1160d5295889925aac9aaa1ac7ca16ae