Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer.
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 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.
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
A
A
Mavrou
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
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K
Brakspear
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
M
M
Hamdollah-Zadeh
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
G
G
Damodaran
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK.
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Babaei-Jadidi
Department of Cellular Pathology, North Bristol NHS Trust, Bristol, UK.
J
J
Oxley
Department of Urological Sciences, North Bristol NHS Trust, Bristol, UK.
D A
DA
Gillatt
Centre for Research in Bioscience, Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.
M R
MR
Ladomery
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
S J
SJ
Harper
1] School of Physiology and Pharmacology, University of Bristol, Bristol, UK [2] Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK.
D O
DO
Bates
School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
S
S
Oltean
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012326:RNA Splicing / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases