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Title: Targeting angiogenesis in prostate cancer
Author: Mavrou, Athina
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Angiogenesis, primarily induced by vascular endothelial growth factor (VEGF). has been shown to be required for prostate cancer development and metastasis. Alternatively spliced isoforms associated with cancer progression have been described in all of the hallmarks of cancer, including angiogenesis. VEGF mRNA is alternatively spliced at the terminal exon, to produce two families of isoforms. The pro- angiogenic family, VEGFxxx. has been shown to be up-regulated in several cancer types including prostate cancer, whereas the antiangiogenic family is preferentially expressed in normal non-angiogenic tissues, but down-regulated in prostate cancer. One of the molecules shown to be involved in the regulation of VEGF alternative splicing is SRPK1. This is a protein kinase that phosphorylates the splicing factor SRSF1 and favours the production of the proangiogenic VEGF isoform. I therefore tested the hypothesis that SRPK1 regulates VEGF mRNA splicing in prostate cancer and that down-regulation of this kinase would increase the production of the anti-angiogenic isoform, preventing angiogenesis and tumour growth. I also tested the hypothesis that SRPK1 and SRSF1 are up-regulated in prostate cancer, given the extensive mis-regulation of splicing events in this malignancy. Studies on prostatectomy samples from patients with prostate cancer showed an up -regulation of SRPK1 and SRSF1 in malignant compared to benign tissues. In addition, a panel of prostate cancer cell lines showed increased expression of SRPK1 when compared with primary prostate epithelial cells. Stable SRPK1 knock-down in PC-3 and LnCap prostate cancer cells and inhibition of SRPK1 using small molecule inhibitors caused a reduction in the pro - angiogenic VEGF expression and splice factor phosphorylation . In vivo, inhibition of SRPK1 by lentiviral knockdown and a small molecule inhibitor resulted in a reduction of prostate tumour growth and decreased vascular density. This study identifies a molecular mechanism that regulates angiogenesis in prostate cancer and provides evidence for the potential use of an SRPK1 inhibitor in the treatment of prostate cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available