Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer

Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer

Author Andrade, Sheila Siqueira Autor UNIFESP Google Scholar
Gouvea, Iuri Estrada Autor UNIFESP Google Scholar
Silva, Mariana Cristina C. Autor UNIFESP Google Scholar
Castro, Eloisa Dognani Autor UNIFESP Google Scholar
de Paula, Claudia A. A. Autor UNIFESP Google Scholar
Okamoto, Debora Autor UNIFESP Google Scholar
Oliveira, Lilian Autor UNIFESP Google Scholar
Peres, Giovani Bravin Autor UNIFESP Google Scholar
Ottaiano, Tatiana Autor UNIFESP Google Scholar
Facina, Gil Autor UNIFESP Google Scholar
Pinto Nazario, Afonso Celso Autor UNIFESP Google Scholar
Campos, Antonio Hugo J. F. M. Google Scholar
Paredes-Gamero, Edgar Julian Autor UNIFESP Google Scholar
Juliano, Maria Autor UNIFESP Google Scholar
da Silva, Ismael D. C. G. Autor UNIFESP Google Scholar
Oliva, Maria Luiza V. Autor UNIFESP Google Scholar
Girao, Manoel J. B. C. Autor UNIFESP Google Scholar
Abstract Background: Breast cancer comprises clinically and molecularly distinct tumor subgroups that differ in cell histology and biology and show divergent clinical phenotypes that impede phase III trials, such as those utilizing cathepsin K inhibitors. Here we correlate the epithelial-mesenchymal-like transition breast cancer cells and cathepsin K secretion with activation and aggregation of platelets. Cathepsin K is up-regulated in cancer cells that proteolyze extracellular matrix and contributes to invasiveness. Although proteolytically activated receptors (PARs) are activated by proteases, the direct interaction of cysteine cathepsins with PARs is poorly understood. In human platelets, PAR-1 and -4 are highly expressed, but PAR-3 shows low expression and unclear functions. Methods: Platelet aggregation was monitored by measuring changes in turbidity. Platelets were immunoblotted with anti-phospho and total p38, Src-Tyr-416, FAK-Tyr-397, and TGF beta monoclonal antibody. Activation was measured in a flow cytometer and calcium mobilization in a confocal microscope. Mammary epithelial cells were prepared from the primary breast cancer samples of 15 women with Luminal-B subtype to produce primary cells. Results: We demonstrate that platelets are aggregated by cathepsin K in a dose-dependent manner, but not by other cysteine cathepsins. PARs-3 and -4 were confirmed as the cathepsin K target by immunodetection and specific antagonists using a fibroblast cell line derived from PARs deficient mice. Moreover, through co-culture experiments, we show that platelets activated by cathepsin K mediated the up-regulation of SHH, PTHrP, OPN, and TGF beta in epithelial-mesenchymal-like cells from patients with Luminal B breast cancer. Conclusions: Cathepsin K induces platelet dysfunction and affects signaling in breast cancer cells.
Keywords Cathepsin K
Breast cancer
Protease activated receptors
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor Associacao Beneficente de Coleta de Sangue (Colsan)
Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
Grant number FAPESP: 2012/19780-3
FAPESP: 2012/19851-8
FAPESP: 2009/53766-5
Date 2016
Published in Bmc Cancer. London, v. 16, p. -, 2016.
ISSN 1471-2407 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent -
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000371668400002

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