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

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dc.contributor.author Andrade, Sheila Siqueira [UNIFESP]
dc.contributor.author Gouvea, Iuri Estrada [UNIFESP]
dc.contributor.author Silva, Mariana Cristina C. [UNIFESP]
dc.contributor.author Castro, Eloisa Dognani [UNIFESP]
dc.contributor.author de Paula, Claudia A. A. [UNIFESP]
dc.contributor.author Okamoto, Debora [UNIFESP]
dc.contributor.author Oliveira, Lilian [UNIFESP]
dc.contributor.author Peres, Giovani Bravin [UNIFESP]
dc.contributor.author Ottaiano, Tatiana [UNIFESP]
dc.contributor.author Facina, Gil [UNIFESP]
dc.contributor.author Pinto Nazario, Afonso Celso [UNIFESP]
dc.contributor.author Campos, Antonio Hugo J. F. M.
dc.contributor.author Paredes-Gamero, Edgar Julian [UNIFESP]
dc.contributor.author Juliano, Maria [UNIFESP]
dc.contributor.author da Silva, Ismael D. C. G. [UNIFESP]
dc.contributor.author Oliva, Maria Luiza V. [UNIFESP]
dc.contributor.author Girao, Manoel J. B. C. [UNIFESP]
dc.date.accessioned 2020-08-21T17:00:11Z
dc.date.available 2020-08-21T17:00:11Z
dc.date.issued 2016
dc.identifier http://dx.doi.org/10.1186/s12885-016-2203-7
dc.identifier.citation Bmc Cancer. London, v. 16, p. -, 2016.
dc.identifier.issn 1471-2407
dc.identifier.uri https://repositorio.unifesp.br/handle/11600/57896
dc.description.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. en
dc.description.sponsorship Associacao Beneficente de Coleta de Sangue (Colsan)
dc.description.sponsorship Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorship Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
dc.description.sponsorship Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
dc.format.extent -
dc.language.iso eng
dc.publisher Biomed Central Ltd
dc.relation.ispartof Bmc Cancer
dc.rights Acesso aberto
dc.subject Cathepsin K en
dc.subject Platelets en
dc.subject Breast cancer en
dc.subject Protease activated receptors en
dc.title Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer en
dc.type Artigo
dc.description.affiliation Univ Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliation COLSAN, Charitable Assoc Blood Collect, BR-04080006 Sao Paulo, SP, Brazil
dc.description.affiliation Univ Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliation Univ Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliation Antonio Prudente Fdn, AC Camargo Canc Ctr, AC Camargo Hosp Biobank, Dept Pathol, BR-01509010 Sao Paulo, SP, Brazil
dc.description.affiliation Univ Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, Brazil
dc.description.sponsorshipID FAPESP: 2012/19780-3
dc.description.sponsorshipID FAPESP: 2012/19851-8
dc.description.sponsorshipID FAPESP: 2009/53766-5
dc.identifier.file WOS000371668400002.pdf
dc.identifier.doi 10.1186/s12885-016-2203-7
dc.description.source Web of Science
dc.identifier.wos WOS:000371668400002
dc.coverage London
dc.citation.volume 16



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