The molecular function of kallikrein‐related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer

Thomas Kryza , Nathalie Bock , Scott Lovell , Anja Rockstroh , Melanie L. Lehman , Adam Lesner , Janaththani Panchadsaram , Lakmali Munasinghage Silva , Srilakshmi Srinivasan , Cameron E. Snell , Elizabeth D. Williams , Ladan Fazli , Martin Gleave , Jyotsna Batra , Colleen Nelson , Edward W. Tate , Jonathan Harris , John D. Hooper , Judith A. Clements

Abstract

Kallikrein‐related peptidase 14 (KLK14) is one of several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumour microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analysed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic and in vitro assays with the goal to identify substrates, related‐signalling pathways and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neo‐adjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression re‐occurred in patients who developed castrate‐resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14‐substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14‐regulated genes (Interleukin 32, midkine, Sox9), particularly an involvement of the MAPK1 and IL1RN pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumours. Additional work is necessary to determine the benefits and implications of targeting/co‐targeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.
Author Thomas Kryza
Thomas Kryza,,
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, Nathalie Bock
Nathalie Bock,,
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, Scott Lovell
Scott Lovell,,
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, Anja Rockstroh
Anja Rockstroh,,
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, Melanie L. Lehman
Melanie L. Lehman,,
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, Adam Lesner (FCh / DET / LBAN)
Adam Lesner,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
, Janaththani Panchadsaram
Janaththani Panchadsaram,,
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, Lakmali Munasinghage Silva
Lakmali Munasinghage Silva,,
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, Srilakshmi Srinivasan
Srilakshmi Srinivasan,,
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, Cameron E. Snell
Cameron E. Snell,,
-
et al.`
Journal seriesMolecular Oncology, ISSN 1574-7891, (N/A 140 pkt)
Issue year2020
Vol14
No1
Pages105-128
Publication size in sheets1.15
Keywords in EnglishKallikrein-related peptidase, prostate cancer, protease, protease-substrate, castrate-resistant prostate cancer, metastasis
ASJC Classification2700 General Medicine; 1306 Cancer Research; 1311 Genetics; 1313 Molecular Medicine
DOIDOI:10.1002/1878-0261.12587
URL https://doi.org/10.1002/1878-0261.12587
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 28-01-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 1.119; WoS Impact Factor: 2018 = 5.962 (2) - 2018=5.497 (5)
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