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Suppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxel

2017-05Journal article Restricted
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dc.contributor.authorSilva, Patrícia M. A.
dc.contributor.authorRibeiro, Nilza
dc.contributor.authorLima, Raquel T.
dc.contributor.authorAndrade, Claudia
dc.contributor.authorDiogo, Vania
dc.contributor.authorTeixeira, Joana
dc.contributor.authorFlorindo, C.
dc.contributor.authorTavares, Alvaro
dc.contributor.authorVasconcelos, M. Helena
dc.contributor.authorBousbaa, Hassan
dc.date.accessioned2019-11-20T15:07:35Z
dc.date.available2019-11-20T15:07:35Z
dc.date.issued2017-05
dc.description.abstractMicrotubule-targeting agents (MTAs) are used extensively for the treatment of diverse types of cancer. They block cancer cells in mitosis through the activation of the spindle assembly checkpoint (SAC), the surveillance mechanism that ensures accurate chromosome segregation at the onset of anaphase. However, the cytotoxic activity of MTAs is limited by premature mitotic exit (mitotic slippage) due to SAC silencing. Here we have explored the dual role of the protein Spindly in chromosome attachments and SAC silencing to analyze the consequences of its depletion on the viability of tumor cells treated with clinically relevant doses of paclitaxel. As expected, siRNA-mediated Spindly suppression induced chromosome misalignment and accumulation of cells in mitosis. Remarkably, these cells were more sensitive to low-doses of paclitaxel. Sensitization was due to an increase in the length of mitotic arrest and high frequency of multinucleated cells, both correlated with an exacerbated post-mitotic cell death response as determined by cell fate profiling. Thus, by affecting both SAC silencing and chromosome attachment, Spindly targeting offers a double-edged sword that potentiates tumor cell killing by clinically relevant doses of paclitaxel, providing a rationale for combination chemotherapy against cancer. (C) 2017 Elsevier B.V. All rights reserved.
dc.description.sponsorshipCESPU - Cooperativa de Ensino Superior Politecnico e Universitario
dc.description.sponsorshipFCT [SFRH/BD/90744/2012]
dc.description.sponsorshipNational Portuguese funding through FCT - Fundação para a Ciência e a Tecnologia [UID/BIM/04773/2013 CBMR]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1016/j.canlet.2017.02.024
dc.identifier.issn0304-3835
dc.identifier.issn1872-7980
dc.identifier.urihttp://hdl.handle.net/10400.1/13117
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier Ireland Ltd
dc.subjectAssembly checkpoint
dc.subjectKinetochore
dc.subjectMitosis
dc.subjectDynein
dc.subjectMad2
dc.subjectInactivation
dc.subjectSegregation
dc.subjectTherapies
dc.subjectCarcinoma
dc.subjectApoptosis
dc.titleSuppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxel
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F90744%2F2012/PT
oaire.citation.endPage42
oaire.citation.startPage33
oaire.citation.titleCancer Letters
oaire.citation.volume394
oaire.fundingStreamSFRH
person.familyNameSilva
person.familyNameFlorindo
person.familyNameTavares
person.givenNamePatrícia
person.givenNameClaudia
person.givenNameAlvaro
person.identifier1445798
person.identifier.ciencia-id4B19-7E26-A047
person.identifier.ciencia-id7812-FEB4-622A
person.identifier.ciencia-idAD12-B7F1-969B
person.identifier.orcid0000-0002-0694-7321
person.identifier.orcid0000-0003-4549-2179
person.identifier.orcid0000-0002-7137-0944
person.identifier.scopus-author-id55855611900
person.identifier.scopus-author-id26531090300
person.identifier.scopus-author-id19036533500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccess
rcaap.typearticle
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relation.isAuthorOfPublication4444e021-d38a-470f-b2d7-35fd2d7c1883
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