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Aberrantly expressed Bruton’s tyrosine kinase preferentially drives metastatic and stem cell-like phenotypes in neuroblastoma cells
- Source :
- Cellular Oncology. 43:1067-1084
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Neuroblastoma, a common childhood tumor, remains one of the most elusive diseases to treat. To date, high-risk neuroblastoma is associated with low survival rates. To address this, novel and more effective therapeutic strategies must continue to be explored. We employed a bioinformatics approach corroborated with in vitro and in vivo data. Samples from neuroblastoma patients were retrieved and immuno-stained for Bruton’s tyrosine kinase (BTK). To evaluate its effect on cellular functions, BTK expression in SK-N-BE(2) and SH-SY5Y neuroblastoma cells was downregulated using gene silencing or inhibition with ibrutinib or acalabrutinib. Xenograft mouse models were used to investigate the in vivo role of BTK in neuroblastoma tumorigenesis. We found that BTK was highly expressed in primary neuroblastoma samples, preferentially in MYCN-amplified neuroblastoma cases, and was associated with a poor prognosis. Immunohistochemical staining of tissues from our neuroblastoma cohort revealed a strong BTK immunoreactivity. We also found that neuroblastoma SK-N-BE(2) and SH-SY5Y cells were sensitive to treatment with ibrutinib and acalabrutinib. Pharmacologic or molecular inhibition of BTK elicited a reduction in the migratory and invasive abilities of neuroblastoma cells, and ibrutinib considerably attenuated the neurosphere-forming ability of neuroblastoma cells. Both inhibitors showed synergism with cisplatin. In vivo assays showed that acalabrutinib effectively inhibited neuroblastoma tumorigenesis. From our data we conclude that BTK is a therapeutically targetable driver of neuroblastoma.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Carcinogenesis
Mice, SCID
medicine.disease_cause
Neuroblastoma
chemistry.chemical_compound
0302 clinical medicine
Cell Movement
Mice, Inbred NOD
hemic and lymphatic diseases
Agammaglobulinaemia Tyrosine Kinase
Neoplasm Metastasis
biology
Caspase 3
General Medicine
Prognosis
Gene Expression Regulation, Neoplastic
Phenotype
Oncology
Pyrazines
030220 oncology & carcinogenesis
Ibrutinib
Benzamides
Neoplastic Stem Cells
Molecular Medicine
Acalabrutinib
Female
Stem cell
Tyrosine kinase
STAT3 Transcription Factor
Antineoplastic Agents
03 medical and health sciences
Cancer stem cell
Cell Line, Tumor
Spheroids, Cellular
medicine
Animals
Humans
Bruton's tyrosine kinase
Neoplasm Invasiveness
neoplasms
medicine.disease
Ki-67 Antigen
030104 developmental biology
chemistry
biology.protein
Cancer research
Cisplatin
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 22113436 and 22113428
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Cellular Oncology
- Accession number :
- edsair.doi.dedup.....63f80046d44eeffd7bc594a863e81631