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

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Title: A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer
Authors: Lovell, S
Zhang, L
Kryza, T
Neodo, A
Bock, N
De Vita, E
Williams, E
Engelsberger, E
Xu, C
Bakker, A
Maneiro, M
Tanaka, R
Bevan, C
Clements, J
Tate, E
Item Type: Journal Article
Abstract: 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 activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. 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.
Issue Date: 16-Jun-2021
Date of Acceptance: 19-May-2021
URI: http://hdl.handle.net/10044/1/89981
DOI: 10.1021/jacs.1c03950
ISSN: 0002-7863
Publisher: American Chemical Society
Start Page: 8911
End Page: 8924
Journal / Book Title: Journal of the American Chemical Society
Volume: 143
Issue: 23
Copyright Statement: © 2021 The Authors. Published by American Chemical Society. This article is availalbe open access under a CC-BY Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Commission of the European Communities
Worldwide Cancer Research
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: 890900
19-0059
N/A
Keywords: General Chemistry
03 Chemical Sciences
Publication Status: Published
Online Publication Date: 2021-06-04
Appears in Collections:Bioengineering
Department of Surgery and Cancer
Chemistry
Biological and Biophysical Chemistry
Faculty of Medicine
Faculty of Natural Sciences



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