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Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1.
J Proteome Res 2016; 15(8):2466-78JP

Abstract

Prostate cancer metastasis to bone is terminal; thus, novel therapies are required to prevent end-stage disease. Kallikrein-related peptidase 4 (KLK4) is a serine protease that is overproduced in localized prostate cancer and is abundant in prostate cancer bone metastases. In vitro, KLK4 induces tumor-promoting phenotypes; however, the underlying proteolytic mechanism is undefined. The protein topography and migration analysis platform (PROTOMAP) was used for high-depth identification of KLK4 substrates secreted by prostate cancer bone metastasis-derived PC-3 cells to delineate the mechanism of KLK4 action in advanced prostate cancer. Thirty-six putative novel substrates were determined from the PROTOMAP analysis. In addition, KLK4 cleaved the established substrate, urokinase-type plasminogen activator, thus validating the approach. KLK4 activated matrix metalloproteinase-1 (MMP1), a protease that promotes prostate tumor growth and metastasis. MMP1 was produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site. KLK4 further liberated an N-terminal product, with purported angiogenic activity, from thrombospondin-1 (TSP1) and cleaved TSP1 in an osteoblast-derived matrix. This is the most comprehensive analysis of the proteolytic action of KLK4 in an advanced prostate cancer model to date, highlighting KLK4 as a potential multifunctional regulator of prostate cancer progression.

Authors+Show Affiliations

Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute , 37 Kent Street, Woolloongabba, Queensland 4102, Australia. Institute of Health and Biomedical Innovation, Queensland University of Technology , 60 Musk Avenue, Kelvin Grove, Queensland 4059, Australia.Institute of Health and Biomedical Innovation, Queensland University of Technology , 60 Musk Avenue, Kelvin Grove, Queensland 4059, Australia.Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute , 37 Kent Street, Woolloongabba, Queensland 4102, Australia. Institute of Health and Biomedical Innovation, Queensland University of Technology , 60 Musk Avenue, Kelvin Grove, Queensland 4059, Australia.Institute of Health and Biomedical Innovation, Queensland University of Technology , 60 Musk Avenue, Kelvin Grove, Queensland 4059, Australia.Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute , 37 Kent Street, Woolloongabba, Queensland 4102, Australia. Institute of Health and Biomedical Innovation, Queensland University of Technology , 60 Musk Avenue, Kelvin Grove, Queensland 4059, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27378148

Citation

Fuhrman-Luck, Ruth A., et al. "Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1." Journal of Proteome Research, vol. 15, no. 8, 2016, pp. 2466-78.
Fuhrman-Luck RA, Stansfield SH, Stephens CR, et al. Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1. J Proteome Res. 2016;15(8):2466-78.
Fuhrman-Luck, R. A., Stansfield, S. H., Stephens, C. R., Loessner, D., & Clements, J. A. (2016). Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1. Journal of Proteome Research, 15(8), pp. 2466-78. doi:10.1021/acs.jproteome.5b01148.
Fuhrman-Luck RA, et al. Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1. J Proteome Res. 2016 08 5;15(8):2466-78. PubMed PMID: 27378148.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1. AU - Fuhrman-Luck,Ruth A, AU - Stansfield,Scott H, AU - Stephens,Carson R, AU - Loessner,Daniela, AU - Clements,Judith A, Y1 - 2016/07/27/ PY - 2016/7/6/entrez PY - 2016/7/6/pubmed PY - 2017/9/26/medline KW - bone metastases KW - kallikrein-related peptidase KW - prostate cancer KW - proteomics KW - substrate SP - 2466 EP - 78 JF - Journal of proteome research JO - J. Proteome Res. VL - 15 IS - 8 N2 - Prostate cancer metastasis to bone is terminal; thus, novel therapies are required to prevent end-stage disease. Kallikrein-related peptidase 4 (KLK4) is a serine protease that is overproduced in localized prostate cancer and is abundant in prostate cancer bone metastases. In vitro, KLK4 induces tumor-promoting phenotypes; however, the underlying proteolytic mechanism is undefined. The protein topography and migration analysis platform (PROTOMAP) was used for high-depth identification of KLK4 substrates secreted by prostate cancer bone metastasis-derived PC-3 cells to delineate the mechanism of KLK4 action in advanced prostate cancer. Thirty-six putative novel substrates were determined from the PROTOMAP analysis. In addition, KLK4 cleaved the established substrate, urokinase-type plasminogen activator, thus validating the approach. KLK4 activated matrix metalloproteinase-1 (MMP1), a protease that promotes prostate tumor growth and metastasis. MMP1 was produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site. KLK4 further liberated an N-terminal product, with purported angiogenic activity, from thrombospondin-1 (TSP1) and cleaved TSP1 in an osteoblast-derived matrix. This is the most comprehensive analysis of the proteolytic action of KLK4 in an advanced prostate cancer model to date, highlighting KLK4 as a potential multifunctional regulator of prostate cancer progression. SN - 1535-3907 UR - https://www.unboundmedicine.com/medline/citation/27378148/Prostate_Cancer_Associated_Kallikrein_Related_Peptidase_4_Activates_Matrix_Metalloproteinase_1_and_Thrombospondin_1_ L2 - https://dx.doi.org/10.1021/acs.jproteome.5b01148 DB - PRIME DP - Unbound Medicine ER -