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.

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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 intra-epithelial 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 VEGF 165 towards the anti-angiogenic splice isoform, VEGF 165 b, 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 VEGF 165 b 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: Sep 16, 2014
• Online Publication Date: Nov 10, 2014
• Publication Date: Aug 13, 2015
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 34
• Pages: 4311-4319
• DOI: https://doi.org/10.1038/onc.2014.360
• Keywords: SRPK1, prostate cancer
• Public URL: https://uwe-repository.worktribe.com/output/829927
• Publisher URL: http://dx.doi.org/10.1038/onc.2014.360