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Prostate‐specific antigen (PSA) is activated by KLK2 in prostate cancer ex vivo models and in prostate‐targeted PSA/KLK2 double transgenic mice
Author(s) -
Williams Simon A.,
Xu Yi,
De Marzo Angelo M.,
Isaacs John T.,
Denmeade Samuel R.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21111
Subject(s) - prostate cancer , du145 , prostate specific antigen , ex vivo , prostate , genetically modified mouse , cancer research , transgene , in vivo , cancer , medicine , biology , lncap , biochemistry , gene , microbiology and biotechnology
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. Prostate 70: 788–796, 2010. © 2010 Wiley‐Liss, Inc.