Tags

Type your tag names separated by a space and hit enter

The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer.
Mol Oncol 2019MO

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.

Authors+Show Affiliations

Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia. Mater Research Institute, The University of Queensland, Woolloongabba Brisbane, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.Faculty of Chemistry, University of Gdansk, 80-308, Gdansk, Poland.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Mater Research Institute, The University of Queensland, Woolloongabba Brisbane, QLD, Australia. Mater Health Services, South Brisbane, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.School of Biomedical Sciences, Faculty of Health, Queensland University of Technology.Mater Research Institute, The University of Queensland, Woolloongabba Brisbane, QLD, Australia. Mater Health Services, South Brisbane, QLD, Australia.Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology. Translational Research Institute, Woolloongabba, QLD, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31630475

Citation

Kryza, Thomas, et al. "The Molecular Function of Kallikrein-related Peptidase 14 Demonstrates a Key Modulatory Role in Advanced Prostate Cancer." Molecular Oncology, 2019.
Kryza T, Bock N, Lovell S, et al. The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer. Mol Oncol. 2019.
Kryza, T., Bock, N., Lovell, S., Rockstroh, A., Lehman, M. L., Lesner, A., ... Clements, J. A. (2019). The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer. Molecular Oncology, doi:10.1002/1878-0261.12587.
Kryza T, et al. The Molecular Function of Kallikrein-related Peptidase 14 Demonstrates a Key Modulatory Role in Advanced Prostate Cancer. Mol Oncol. 2019 Oct 20; PubMed PMID: 31630475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer. AU - Kryza,Thomas, AU - Bock,Nathalie, AU - Lovell,Scott, AU - Rockstroh,Anja, AU - Lehman,Melanie L, AU - Lesner,Adam, AU - Panchadsaram,Janaththani, AU - Silva,Lakmali Munasinghage, AU - Srinivasan,Srilakshmi, AU - Snell,Cameron E, AU - Williams,Elizabeth D, AU - Fazli,Ladan, AU - Gleave,Martin, AU - Batra,Jyotsna, AU - Nelson,Colleen, AU - Tate,Edward W, AU - Harris,Jonathan, AU - Hooper,John D, AU - Clements,Judith A, Y1 - 2019/10/20/ PY - 2019/05/23/received PY - 2019/09/06/revised PY - 2019/09/22/accepted PY - 2019/10/21/entrez PY - 2019/10/21/pubmed PY - 2019/10/21/medline KW - Castrate-resistant prostate cancer KW - Kallikrein-related peptidase KW - Prostate cancer KW - Protease KW - Protease-substrate KW - metastasis JF - Molecular oncology JO - Mol Oncol N2 - 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. SN - 1878-0261 UR - https://www.unboundmedicine.com/medline/citation/31630475/The_molecular_function_of_kallikrein-related_peptidase_14_demonstrates_a_key_modulatory_role_in_advanced_prostate_cancer L2 - https://doi.org/10.1002/1878-0261.12587 DB - PRIME DP - Unbound Medicine ER -