Aberrantly expressed Bruton’s tyrosine kinase preferentially drives metastatic and stem cell-like phenotypes in neuroblastoma cells
Journal
Cellular Oncology
Journal Volume
43
Journal Issue
6
Pages
1067-1084
Date Issued
2020
Author(s)
Abstract
Purpose: 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.
Methods: 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.
Results: 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.
Conclusions: From our data we conclude that BTK is a therapeutically targetable driver of neuroblastoma.
Subjects
Acalabrutinib
Bruton’s tyrosine kinase
Cancer stem cells
Ibrutinib
Metastasis
Neuroblastoma
Pediatric brain tumor
SDGs
Other Subjects
acalabrutinib; Bruton tyrosine kinase; cisplatin; ibrutinib; acalabrutinib; antineoplastic agent; benzamide derivative; caspase 3; cisplatin; Ki 67 antigen; protein kinase B; pyrazine derivative; STAT3 protein; adult; animal experiment; animal model; animal tissue; Article; bioinformatics; cancer patient; cancer prognosis; cancer stem cell; carcinogenesis; cell function; cell invasion; cohort analysis; controlled study; data analysis software; down regulation; drug potentiation; enzyme inhibition; female; gene amplification; gene expression; gene silencing; human; human cell; human tissue; immunofluorescence test; immunohistochemistry; immunoreactivity; in vitro study; in vivo study; metastasis; migration inhibition; mouse; neuroblastoma; neuroblastoma cell; nonhuman; phenotype; priority journal; protein expression; SH-SY5Y cell line; SK-N-BE(2) cell line; tumor xenograft; animal; cancer stem cell; cell motion; drug effect; enzymology; gene expression regulation; genetics; male; metabolism; metastasis; multicellular spheroid; neuroblastoma; nonobese diabetic mouse; pathology; prognosis; SCID mouse; tumor cell line; tumor invasion; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Carcinogenesis; Caspase 3; Cell Line, Tumor; Cell Movement; Cisplatin; Female; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Neuroblastoma; Phenotype; Prognosis; Proto-Oncogene Proteins c-akt; Pyrazines; Spheroids, Cellular; STAT3 Transcription Factor
Publisher
Springer Science and Business Media B.V.
Type
journal article