Effect of Free-Prostate Specific Antigen (f-PSA) on Angiogenic Growth Factor Expression
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Background: Prostate-specific antigen (PSA) is extensively used as a biomarker for early diagnosis and management of prostate cancer. The physiological function of PSA in liquefying the seminal clot is well understood. However, the role of PSA in growth and progression of prostate cancer still remains unknown. PSA has been reported to have anti-angiogenic and anti-tumorigenic activities in both in vitro and in vivo studies. The aim of this study is to examine the effects of PSA on angiogenic growth factor expression in epithelial and endothelial cells. Methods: Column chromatography was used to purify free-PSA (f-PSA) from human seminal plasma. Confluent monolayers of prostate cancer epithelial cell line, PC-3M and endothelial cells, HUVEC were treated with f-PSA at different concentrations and for various time periods. q-PCR studies were performed to determine the changes in expression of various genes that are known to regulate tumor growth and metastasis. The following genes were examined for the above studies: VEGF, KDR, FGF-2, Ang-1, FAK, Twist-1, p38 MAPK, Pim-1 and PTEN. Gene expression studies in PC-3M cells were validated by determining the changes in secreted VEGF protein on f-PSA treatment by ELISA. Results: Treatment with f-PSA suppressed the expression of pro-angiogenic and pro-migratory genes in both cell lines. The optimum treatment conditions in PC-3M cells included 1μM or 10μM f-PSA treatment for 48 hours. Gene expression in HUVEC cells was significantly inhibited after 24 hours treatment with 10μM f-PSA. Dose-dependent response was gene specific. In contrast to VEGF gene expression, there was an increase in secreted VEGF protein on f-PSA treatment. However, this anomaly needs further investigation. Conclusion: f-PSA affects the expression of angiogenic growth factors and genes involved in migration and metastasis in both tumor epithelial cells and vasculature cells. The concentration of f-PSA used for the experiments is relevant since it is similar to PSA concentrations in the extracellular fluid of the prostate and in primary prostate cancer. This study supports the hypothesis that PSA potentially has anti-angiogenic and anti-metastatic activities in prostate cancer.