Abstract 2749: SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer

Abstract

Abstract Angiogenesis is required for tumor growth and is induced principally by 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. In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by 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 to benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in prostate cancer may be under control of SRPK1 activity. SRPK1 levels were up-regulated in several prostate cancer cell lines in comparison with normal prostate epithelial cells. A switch in the expression of VEGF165 towards the anti-angiogenic isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knock-down (KD). PC-3 -SRPK1 KD cells resulted in tumors 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. Moreover, VEGF over-expression from a splicing-insensitive construct in PC-3/SRPK1 KD cells rescued tumor growth. Small molecule inhibitors of SRPK1 are able to switch splicing towards the anti-angiogenic isoform, VEGF165b in PC3 cells in vitro and decrease tumor growth when administered intraperitoneally in vivo in a mouse model of orthotopic prostate cancer. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumor angiogenesis by regulation of VEGF splicing can alter prostate tumor growth and supports further studies into the use of SRPK1 inhibition as a potential anti-angiogenic therapy in prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Athina Mavrou, Dave Bates, Sebastian Oltean. SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2014-2749