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Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer

Mavrou, A.; Brakspear, K.; Hamdollah-Zadeh, M.; Damodaran, G.; Babaei-Jadidi, R.; Oxley, J.; Gillatt, D.A.; Ladomery, M.R.; Harper, S.J.; Bates, D.O.; Oltean, S.

Authors

A. Mavrou

K. Brakspear

M. Hamdollah-Zadeh

G. Damodaran

J. Oxley

D.A. Gillatt

M.R. Ladomery

S.J. Harper

DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology

S. Oltean



Abstract

Angiogenesis is required for tumour growth and is induced principally by vascular endothelial growth factor A (VEGF-A). VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer (PCa). In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by serine–arginine protein kinase 1 (SRPK1). Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intraepithelial neoplasia lesions as well as malignant adenocarcinoma compared with benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in PCa may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knockdown (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small-molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC-3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of PCa. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies for the use of SRPK1 inhibition as a potential anti-angiogenic therapy in PCa.

Journal Article Type Article
Acceptance Date Dec 16, 2014
Online Publication Date Nov 10, 2014
Publication Date Aug 13, 2015
Deposit Date Jul 10, 2018
Print ISSN 0950-9232
Electronic ISSN 1476-5594
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 34
Issue 33
Pages 4311-4319
DOI https://doi.org/10.1038/onc.2014.360
Public URL https://nottingham-repository.worktribe.com/output/1114831
Publisher URL https://www.nature.com/articles/onc2014360
PMID 25381816