A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer
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, an...
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Published in | Journal of the American Chemical Society Vol. 143; no. 23; pp. 8911 - 8924 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
16.06.2021
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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. |
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AbstractList | 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. 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. |
Author | Lovell, Scott Neodo, Anna Xu, Congyi Bevan, Charlotte L Clements, Judith A Tate, Edward W Bakker, Alexander T Tanaka, Reiko J Bock, Nathalie Engelsberger, Elisabeth Kryza, Thomas Maneiro, Maria Zhang, Leran De Vita, Elena Williams, Elizabeth D |
AuthorAffiliation | Queensland University of Technology, Translational Research Institute Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation and School of Biomedical Sciences, Faculty of Health Department of Bioengineering The Francis Crick Institute Department of Chemistry, Molecular Sciences Research Hub Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine Imperial College London, Hammersmith Hospital |
AuthorAffiliation_xml | – name: Department of Bioengineering – name: Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine – name: Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation and School of Biomedical Sciences, Faculty of Health – name: Queensland University of Technology, Translational Research Institute – name: Imperial College London, Hammersmith Hospital – name: The Francis Crick Institute – name: Department of Chemistry, Molecular Sciences Research Hub |
Author_xml | – sequence: 1 givenname: Scott surname: Lovell fullname: Lovell, Scott organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 2 givenname: Leran surname: Zhang fullname: Zhang, Leran organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 3 givenname: Thomas surname: Kryza fullname: Kryza, Thomas organization: Queensland University of Technology, Translational Research Institute – sequence: 4 givenname: Anna surname: Neodo fullname: Neodo, Anna organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 5 givenname: Nathalie surname: Bock fullname: Bock, Nathalie organization: Queensland University of Technology, Translational Research Institute – sequence: 6 givenname: Elena surname: De Vita fullname: De Vita, Elena organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 7 givenname: Elizabeth D orcidid: 0000-0002-3364-6655 surname: Williams fullname: Williams, Elizabeth D organization: Queensland University of Technology, Translational Research Institute – sequence: 8 givenname: Elisabeth surname: Engelsberger fullname: Engelsberger, Elisabeth organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 9 givenname: Congyi surname: Xu fullname: Xu, Congyi organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 10 givenname: Alexander T surname: Bakker fullname: Bakker, Alexander T organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 11 givenname: Maria orcidid: 0000-0001-6229-9157 surname: Maneiro fullname: Maneiro, Maria organization: Department of Chemistry, Molecular Sciences Research Hub – sequence: 12 givenname: Reiko J surname: Tanaka fullname: Tanaka, Reiko J organization: Department of Bioengineering – sequence: 13 givenname: Charlotte L orcidid: 0000-0002-7533-0552 surname: Bevan fullname: Bevan, Charlotte L organization: Imperial College London, Hammersmith Hospital – sequence: 14 givenname: Judith A surname: Clements fullname: Clements, Judith A organization: Queensland University of Technology, Translational Research Institute – sequence: 15 givenname: Edward W orcidid: 0000-0003-2213-5814 surname: Tate fullname: Tate, Edward W email: e.tate@imperial.ac.uk organization: The Francis Crick Institute |
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SubjectTerms | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Coumarins - chemistry Coumarins - pharmacology Drug Resistance, Neoplasm - drug effects Drug Screening Assays, Antitumor Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Kallikreins - antagonists & inhibitors Kallikreins - metabolism Male Molecular Structure Prostate-Specific Antigen - antagonists & inhibitors Prostate-Specific Antigen - metabolism Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology |
Title | A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer |
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