Targeting the angiogenic 'splice' switch; inhibition of SRPK1 as a novel therapeutic approach in prostate cancer

Abstract

Pathological angiogenesis occurs when the balance between pro-angiogenic and anti-angiogenic factors is tipped enabling an angiogenic switch. VEGF-A is the primary inducer of angiogenesis but is alternatively spliced at the pre-mRNA level to produce pro-angiogenic and anti-angiogenic isoforms. In previous work we showed that the balance of VEGF-A isoforms is regulated by SRSF1, which is regulated by phosphorylation from SRPK1 in renal epithelial cells, colon cancer cells, retinal epithelial cells and melanoma cells. SRPK1 and SRSF1 promote expression of pro-angiogenic VEGF-A 165 a and knockdown or inhibition of SRPK1 switches this balance towards anti-angiogenic VEGF-A 165 b, which inhibits angiogenesis and tumor growth in colon cancer and melanoma cells. In our recent study, Mavrou et al ., 2014, we report that SRPK1 expression is upregulated in both prostatic intraepithelial neoplasia and malignant tissue sections from patients with radical prostatectomy. Knockdown or inhibition of SRPK1 with small molecule inhibitors leads to a splicing switch towards anti-angiogenic VEGF-A in PC-3 cells, a reduction in angiogenesis and inhibition of tumor growth in xenograft models. Specifically inhibiting pro-angiogenic VEGF-A splice isoforms through targeted inhibition of the splicing kinase SRPK1 is a novel approach which could enable development of therapies that are safer and more efficacious than current drugs. This study provides proof-of-concept for modulation of SRPK1 to normalise the endogenous VEGF-A splicing balance, enabling inhibition of angiogenesis and tumor growth in prostate cancer. Here, we discuss our recent findings and ongoing work to develop these findings into a novel therapeutic approach.