Prostate cancer metastasis to bone is terminal; novel therapies are required to prevent end-stage disease. Kallikrein-related peptidase 4 (KLK4) is a serine protease that is over-produced in localized prostate cancer and is abundant in prostate cancer bone metastases. In vitro, KLK4 induces tumor-promoting phenotypes; however, the underlying proteolytic mechanism is undefined. The PROtein TOpography and Migration Analysis Platform (PROTOMAP) was used for high-depth identification of KLK4 substrates secreted by prostate cancer bone metastasis-derived PC-3 cells, to delineate the mechanism of KLK4 action in advanced prostate cancer. Thirty-six putative novel substrates were determined from the PROTOMAP analysis. In addition, KLK4 cleaved the established substrate, urokinase-type plasminogen activator (uPA), thus validating the approach. KLK4 activated matrix metalloproteinase-1 (MMP1), a protease which promotes prostate tumor growth and metastasis. MMP1 was produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site. KLK4 further liberated an N-terminal product, with purported angiogenic activity, from thrombospondin-1 (TSP1), and cleaved TSP1 in an osteoblast-derived matrix. This is the most comprehensive analysis of the proteolytic action of KLK4 in an advanced prostate cancer model to date, highlighting KLK4 as a potential multi-functional regulator of prostate cancer progression.
Journal of proteome research. 2016 Jul 05 [Epub ahead of print]
Ruth Anna Fuhrman-Luck, Scott Hunton Stansfield, Carson Ryan Stephens, Daniela Loessner, Judith A Clements