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.citation.volume16
dc.contributor.authorAndrade, Sheila Siqueira [UNIFESP]
dc.contributor.authorGouvea, Iuri Estrada [UNIFESP]
dc.contributor.authorSilva, Mariana Cristina C. [UNIFESP]
dc.contributor.authorCastro, Eloisa Dognani [UNIFESP]
dc.contributor.authorde Paula, Claudia A. A. [UNIFESP]
dc.contributor.authorOkamoto, Debora [UNIFESP]
dc.contributor.authorOliveira, Lilian [UNIFESP]
dc.contributor.authorPeres, Giovani Bravin [UNIFESP]
dc.contributor.authorOttaiano, Tatiana [UNIFESP]
dc.contributor.authorFacina, Gil [UNIFESP]
dc.contributor.authorPinto Nazario, Afonso Celso [UNIFESP]
dc.contributor.authorCampos, Antonio Hugo J. F. M.
dc.contributor.authorParedes-Gamero, Edgar Julian [UNIFESP]
dc.contributor.authorJuliano, Maria [UNIFESP]
dc.contributor.authorda Silva, Ismael D. C. G. [UNIFESP]
dc.contributor.authorOliva, Maria Luiza V. [UNIFESP]
dc.contributor.authorGirao, Manoel J. B. C. [UNIFESP]
dc.coverageLondon
dc.date.accessioned2020-08-21T17:00:11Z
dc.date.available2020-08-21T17:00:11Z
dc.date.issued2016
dc.description.abstractBackground: 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.affiliationUniv Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationCOLSAN, Charitable Assoc Blood Collect, BR-04080006 Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationAntonio Prudente Fdn, AC Camargo Canc Ctr, AC Camargo Hosp Biobank, Dept Pathol, BR-01509010 Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipAssociacao Beneficente de Coleta de Sangue (Colsan)
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorshipCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
dc.description.sponsorshipIDFAPESP: 2012/19780-3
dc.description.sponsorshipIDFAPESP: 2012/19851-8
dc.description.sponsorshipIDFAPESP: 2009/53766-5
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.1186/s12885-016-2203-7
dc.identifier.citationBmc Cancer. London, v. 16, p. -, 2016.
dc.identifier.doi10.1186/s12885-016-2203-7
dc.identifier.fileWOS000371668400002.pdf
dc.identifier.issn1471-2407
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/57896
dc.identifier.wosWOS:000371668400002
dc.language.isoeng
dc.publisherBiomed Central Ltd
dc.relation.ispartofBmc Cancer
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectCathepsin Ken
dc.subjectPlateletsen
dc.subjectBreast canceren
dc.subjectProtease activated receptorsen
dc.titleCathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast canceren
dc.typeinfo:eu-repo/semantics/article
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