Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma

M. V. Gammons*, R. Lucas, R. Dean, S. E. Coupland, S. Oltean, D. O. Bates

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

57 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)477-485
Number of pages9
JournalBritish Journal of Cancer
Volume111
Issue number3
DOIs
Publication statusPublished - 29 Jul 2014

Fingerprint Dive into the research topics of 'Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma'. Together they form a unique fingerprint.

Cite this