Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma
| Autor: | Katia Balmas Bourloud, Nadja Chevalier, Annick Mühlethaler-Mottet, Jean-Marc Joseph, Nicolas Jauquier, Marjorie Flahaut, Nicole Gross, Raffaele Renella, Katya Nardou, David Barras, Christian Widmann |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Retinal dehydrogenase Retinoic acid Gene Expression Aldehyde dehydrogenase Pharmacology Stem cell marker Aldehyde Dehydrogenase 1 Family ALDH1A2 Gene Knockout Techniques Mice Neuroblastoma 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Neurosphere Genetics Animals Humans Medicine biology business.industry Retinal Dehydrogenase Aldehyde Dehydrogenase Prognosis Aldehyde Oxidoreductases Enzyme Activation Isoenzymes ALDH1A1 Disease Models Animal Phenotype 030104 developmental biology Oncology chemistry Disease Progression biology.protein Cancer research Heterografts Transcriptome business Research Article |
| Zdroj: | Bmc Cancer, vol. 16, no. 1, pp. 781 BMC Cancer |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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