A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer

Scott Lovell, Leran Zhang, Thomas Kryza, Anna Neodo, Nathalie Bock, Elena De Vita, Elizabeth D Williams, Elisabeth Engelsberger, Congyi Xu, Alexander T Bakker, Maria Maneiro, Reiko J Tanaka, Charlotte L Bevan, Judith A Clements, Edward W Tate

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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.

Original languageEnglish
Pages (from-to)8911-8924
Number of pages14
JournalJournal of the American Chemical Society
Volume143
Issue number23
DOIs
Publication statusPublished - 16 Jun 2021

Keywords

  • Antineoplastic Agents/chemistry
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Coumarins/chemistry
  • Drug Resistance, Neoplasm/drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors/chemistry
  • Humans
  • Kallikreins/antagonists & inhibitors
  • Male
  • Molecular Structure
  • Prostate-Specific Antigen/antagonists & inhibitors
  • Prostatic Neoplasms/drug therapy

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