RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance.

Details

Serval ID
serval:BIB_46972C52928F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance.
Journal
Oncogene
Author(s)
Salm F., Cwiek P., Ghosal A., Lucia Buccarello A., Largey F., Wotzkow C., Höland K., Styp-Rekowska B., Djonov V., Zlobec I., Bodmer N., Gross N., Westermann F., Schäfer S.C. , Arcaro A.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
32
Number
34
Pages
3944-3953
Language
english
Notes
Publication types: Journal Article; PDF : original article
Abstract
Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB.
Pubmed
Web of science
Open Access
Yes
Create date
20/09/2013 17:21
Last modification date
20/08/2019 13:52
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