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Br J Cancer. 2014 Jul 29;111(3):477-85. doi: 10.1038/bjc.2014.342. Epub 2014 Jul 10.

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

Author information

1
Microvascular Research Laboratories, School of Physiology and Pharmacology, Preclinical Veterinary Sciences Building, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
2
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
3
1] Microvascular Research Laboratories, School of Physiology and Pharmacology, Preclinical Veterinary Sciences Building, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK [2] Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK.

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.

PMID:
25010863
PMCID:
PMC4119992
DOI:
10.1038/bjc.2014.342
[Indexed for MEDLINE]
Free PMC Article
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