Prostate-specific antigen (PSA) is activated by KLK2 in prostate cancer ex vivo models and in prostate-targeted PSA/KLK2 double transgenic mice.

摘要

BACKGROUND: Prostate-specific antigen (PSA) is a serine protease secreted as a zymogen. Previously, cell-free biochemical studies have identified various kallikreins (KLK) as candidate activating proteases. In this study, KLK2-mediated activation of PSA in cell-based in vitro, xenograft, and transgenic models was evaluated. METHODS: Du145-derived PSA- or KLK2-expressing clones were coincubated in vitro and in vivo to evaluate KLK2-induced PSA activity. While mice possess orthologs of KLK4-15, they do not have functional orthologs of PSA or KLK2. Therefore, transgenic animals expressing PSA or both PSA and KLK2 were generated to assess orthotopic PSA activation. RESULTS: PSA is activated by KLK2 when the cells are physically in contact, and through co-conditioned media. In vivo, the free (inactive PSA) to total (active + inactive PSA) ratio in the blood is decreased when PSA and KLK2-expressing cells are co-inoculated subcutaneously, suggesting increased active PSA. Additionally, double-transgenic mice expressing both genes in the prostate produce more active PSA compared to single transgenic animals. A longitudinal evaluation over a 2-year period demonstrated no morphologic changes (i.e., no PIN or prostate cancer) due to PSA or PSA/KLK2 double transgene expression relative to non-transgenic mice. CONCLUSIONS: These data demonstrate, with biologically relevant models, that KLK2 is the protease responsible for activating PSA. While PSA is involved in the processing and release of a number of important growth factors, our results suggest that active PSA is not sufficient to induce the development of prostate cancer or prostate cancer precursors in aging PSA transgenic mice.