A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer [article]

Scott Lovell, Leran Zhang, Thomas Kryza, Anna Neodo, Nathalie Bock, Elizabeth D Williams, Elisabeth Engelsberger, Congyi Xu, Alexander T Bakker, Elena De Vita, Maria Maneiro, Reiko J Tanaka (+3 others)
2021 bioRxiv   pre-print
Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network, the KLK activome, with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel
more » ... ased probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.
doi:10.1101/2021.04.15.439906 fatcat:4syvjbliffcy5i3x65pbfs24wm