UM
Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy
Ling L.4; Tan S.K.3; Goh T.H.4; Cheung E.3; Nurcombe V.4; van Wijnen A.J.2; Cool S.M.4
2015-07-23
Source PublicationMolecular Cancer
ISSN14764598
Volume14Issue:1
AbstractBackground: Aberrant activation of fibroblast growth factor receptors (FGFRs) deregulates cell proliferation and promotes cell survival, and may predispose to tumorigenesis. Therefore, selective inactivation of FGFRs is an important strategy for cancer therapy. Here as a proof-of-concept study, we developed a FGFR1 neutralizing antisera, IMB-R1, employing a novel strategy aimed at preventing the access of essential heparan sulfate (HS) co-receptors to the heparin-binding domain on FGFR1. Methods: The mRNA and protein expression level of FGFR1 and other FGFRs were examined in several lines of breast cancer and osteosarcoma cells and corresponding normal cells using Taqman real-time quantitative PCR and Western blot analysis. The specificity of IMB-R1 against FGFR1 was assessed with various ELISA-based approaches and Receptor Tyrosine Kinase array. Proliferation assay and apoptosis analysis were performed to assess the effect of IMB-R1 on cancer cell growth and apoptosis, respectively, in comparison with known FGFR1 inhibitors. The IMB-R1 induced alteration of intracellular signaling and gene expression were analysed using Western blot and microarray approaches. Immunohistochemical staining of FGFR1 using IMB-R1 were carried out in different cancer tissues from clinical patients. Throughout the study, statistical differences were determined by Student's t test where appropriate and reported when a p value was less than 0.05. Results: We demonstrate that IMB-R1 is minimally cross-reactive for other FGFRs, and that it potently and specifically inhibits binding of heparin to FGFR1. Furthermore, IMB-R1 blocks the interaction of FGF2 with FGFR1, the kinase activity of FGFR1 and activation of intracellular FGFR signaling. Cancer cells treated with IMB-R1 displayed impaired FGF2 signaling, were unable to grow and instead underwent apoptosis. IMB-R1-induced cell death correlated with a disruption of antioxidative defense networks and increased expression of several tumor suppressors and apoptotic proteins, including p53. Immunostaining with IMB-R1 was stronger in human cancer tissues in which the FGFR1 gene is amplified. Conclusion: Our study suggests that blocking HS interaction with the heparin-binding domains of FGFR1 inhibited cancer cell growth, which can be an attractive strategy to inactivate cancer-related heparin-binding proteins.
KeywordCell death Cell growth Heparan sulfate Neutralizing antibody Targeted therapy Tumor
DOI10.1186/s12943-015-0391-4
URLView the original
Language英語
Fulltext Access
Citation statistics
Cited Times [WOS]:7   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Yong Loo Lin School of Medicine
2.Mayo Clinic
3.A-Star, Genome Institute of Singapore
4.A-Star, Institute of Medical Biology
5.Universidade de Macau
Recommended Citation
GB/T 7714
Ling L.,Tan S.K.,Goh T.H.,et al. Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy[J]. Molecular Cancer,2015,14(1).
APA Ling L..,Tan S.K..,Goh T.H..,Cheung E..,Nurcombe V..,...&Cool S.M..(2015).Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy.Molecular Cancer,14(1).
MLA Ling L.,et al."Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy".Molecular Cancer 14.1(2015).
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Ling L.]'s Articles
[Tan S.K.]'s Articles
[Goh T.H.]'s Articles
Baidu academic
Similar articles in Baidu academic
[Ling L.]'s Articles
[Tan S.K.]'s Articles
[Goh T.H.]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Ling L.]'s Articles
[Tan S.K.]'s Articles
[Goh T.H.]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.