Document Detail


Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma.
MedLine Citation:
PMID:  25010863     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background:Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis-targeting splicing factor kinases that are highly expressed in melanomas.Methods:We used RT-PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo.Results:In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro.Conclusions:These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.British Journal of Cancer advance online publication, 10 July 2014; doi:10.1038/bjc.2014.342 www.bjcancer.comPublished online 8 July 2014.
Authors:
M V Gammons; R Lucas; R Dean; S E Coupland; S Oltean; D O Bates
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-10
Journal Detail:
Title:  British journal of cancer     Volume:  -     ISSN:  1532-1827     ISO Abbreviation:  Br. J. Cancer     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-7-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370635     Medline TA:  Br J Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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