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Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone
BACKGROUND: The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and s...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658578/ https://www.ncbi.nlm.nih.gov/pubmed/31172267 http://dx.doi.org/10.1007/s00432-019-02950-y |
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author | Liang, Weiping Wang, Fuhao Chen, Qiuyan Dai, Jinlu Escara-Wilke, June Keller, Evan T. Zimmermann, Johann Hong, Ni Lu, Yi Zhang, Jian |
author_facet | Liang, Weiping Wang, Fuhao Chen, Qiuyan Dai, Jinlu Escara-Wilke, June Keller, Evan T. Zimmermann, Johann Hong, Ni Lu, Yi Zhang, Jian |
author_sort | Liang, Weiping |
collection | PubMed |
description | BACKGROUND: The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. METHODS: CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. RESULTS: We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). CONCLUSION: The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa. |
format | Online Article Text |
id | pubmed-6658578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-66585782019-08-07 Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone Liang, Weiping Wang, Fuhao Chen, Qiuyan Dai, Jinlu Escara-Wilke, June Keller, Evan T. Zimmermann, Johann Hong, Ni Lu, Yi Zhang, Jian J Cancer Res Clin Oncol Original Article – Cancer Research BACKGROUND: The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. METHODS: CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. RESULTS: We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). CONCLUSION: The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa. Springer Berlin Heidelberg 2019-06-06 2019 /pmc/articles/PMC6658578/ /pubmed/31172267 http://dx.doi.org/10.1007/s00432-019-02950-y Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article – Cancer Research Liang, Weiping Wang, Fuhao Chen, Qiuyan Dai, Jinlu Escara-Wilke, June Keller, Evan T. Zimmermann, Johann Hong, Ni Lu, Yi Zhang, Jian Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title | Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title_full | Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title_fullStr | Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title_full_unstemmed | Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title_short | Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone |
title_sort | targeting cathepsin k diminishes prostate cancer establishment and growth in murine bone |
topic | Original Article – Cancer Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658578/ https://www.ncbi.nlm.nih.gov/pubmed/31172267 http://dx.doi.org/10.1007/s00432-019-02950-y |
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