TY - JOUR
T1 - Aberrantly expressed Bruton’s tyrosine kinase preferentially drives metastatic and stem cell-like phenotypes in neuroblastoma cells
AU - Pikatan, Narpati Wesa
AU - Liu, Yen Lin
AU - Bamodu, Oluwaseun Adebayo
AU - Hsiao, Michael
AU - Hsu, Wen Ming
AU - Haryana, Sofia Mubarika
AU - Sutaryo,
AU - Chao, Tsu Yi
AU - Yeh, Chi Tai
N1 - Funding Information:
The authors thank the research assistants at the Core Facility Center, Department of Medical Research, Taipei Medical University - Shuang Ho Hospital, especially Mr. Iat-Hang Fong and Mr. Sam Huang, for their technical assistance with cell-based assays. The authors also thank Dr. Alexander TH Wu and Mr. Oliver Huang for their interest and constructive advice in the animal experimental designs and their skillful technical support of this project. This manuscript was edited by Wallace Academic Editing.
Funding Information:
This work was supported by the National Science Council of Taiwan: Tsu-Yi Chao (MOST105-2314-B038-080 and MOST 108-2314-B-038-051-MY3). It was also supported by a grant from National Taiwan University Hospital: Wen-Ming Hsu (107-S3825). Acknowledgements
Publisher Copyright:
© 2020, International Society for Cellular Oncology.
PY - 2020/12
Y1 - 2020/12
N2 - 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. Graphical abstract: [Figure not available: see fulltext.]
AB - 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. Graphical abstract: [Figure not available: see fulltext.]
KW - Acalabrutinib
KW - Bruton’s tyrosine kinase
KW - Cancer stem cells
KW - Ibrutinib
KW - Metastasis
KW - Neuroblastoma
KW - Pediatric brain tumor
UR - http://www.scopus.com/inward/record.url?scp=85088502008&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088502008&partnerID=8YFLogxK
U2 - 10.1007/s13402-020-00541-5
DO - 10.1007/s13402-020-00541-5
M3 - Article
C2 - 32705581
AN - SCOPUS:85088502008
VL - 43
SP - 1067
EP - 1084
JO - Cellular oncology (Dordrecht)
JF - Cellular oncology (Dordrecht)
SN - 2211-3428
IS - 6
ER -