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Cancer LettersVolume 394, 28 May 2017, Pages 33-42

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

  • Silva, P.M.A.,
  • Ribeiro, N.,
  • Lima, R.T.,
  • Andrade, C.,
  • Diogo, V.,
  • Teixeira, J.,
  • Florindo, C.,
  • Tavares, Á.,
  • Vasconcelos, M.H.,
  • Bousbaa, H.
  • View Correspondence (jump link)
  • aCESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, Gandra, PRD 4585-116, Portugal
  • bCentre for Biomedical Research (CBMR), University of Algarve, Faro, 8005-139, Portugal
  • cDepartamento Ciências Biomédicas e Medicina, University of Algarve, Faro, 8005-139, Portugal
  • di3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Porto, Portugal
  • eCancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Portugal
  • fDepartment of Pathology, FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal
  • gCEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal
  • hLaboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Porto, Portugal
  • iCentro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, Porto, 4050-123, Portugal

Abstract

Microtubule-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. © 2017 Elsevier B.V.

Author keywords

ApoptosisCancer cellsCell cyclePaclitaxelSpindle assembly checkpointSpindly

Indexed keywords

EMTREE drug terms:paclitaxelproteinprotein spindlysmall interfering RNAunclassified drugcarrier proteinpaclitaxelspindly protein, humantubulin modulator
EMTREE medical terms:antineoplastic activityArticlecancer cellcell deathcell fatecell viabilitychromosomecontrolled studycorrelational studydrug responsedrug sensitizationgene silencinghumanhuman cellM phase cell cycle checkpointmitosis inhibitionmultinuclear cellprotein targetingtumor cellA-549 cell lineapoptosisdose responsedown regulationdrug effectsgene expression regulationgenetic transfectiongeneticsLung Neoplasmsmetabolismmitosis indexpathologyRNA interferencespindle apparatus
MeSH:A549 CellsApoptosisCarrier ProteinsDose-Response Relationship, DrugDown-RegulationGene Expression Regulation, NeoplasticHumansLung NeoplasmsM Phase Cell Cycle CheckpointsMitotic IndexPaclitaxelRNA InterferenceSpindle ApparatusTransfectionTubulin Modulators

Chemicals and CAS Registry Numbers:

paclitaxel, 33069-62-4; protein, 67254-75-5; carrier protein, 80700-39-6;

Carrier Proteins; Paclitaxel; spindly protein, human; Tubulin Modulators

Funding details

Funding sponsor Funding number Acronym
Cooperativa de Ensino Superior Politécnico e Universitário
Fundação para a Ciência e a Tecnologia
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  • 1

    This work was funded by CESPU ? Cooperativa de Ensino Superior Polit?cnico e Universit?rio under the project ?SpindlyTarget-CESPU-2016?. Patr?cia M.A. Silva is a PhD fellowship holder from FCT (SFRH/BD/90744/2012), and partially supported by national Portuguese funding through FCT - Funda??o para a Ci?ncia e a Tecnologia, project ref. UID/BIM/04773/2013 CBMR. We thank the anonymous Reviewers for their comments and constructive criticism.

  • ISSN: 03043835
  • CODEN: CALED
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1016/j.canlet.2017.02.024
  • PubMed ID: 28249757
  • Document Type: Article
  • Publisher: Elsevier Ireland Ltd

  Bousbaa, H.; Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, CESPU, Rua Central da Gandra 1317, Gandra, Paredes, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.

Cited by 6 documents

Silva, P.M.A. , Delgado, M.L. , Ribeiro, N.
Spindly and Bub3 expression in oral cancer: Prognostic and therapeutic implications
(2019) Oral Diseases
Zeng, X. , Xu, W.K. , Lok, T.M.
Imbalance of the spindle-assembly checkpoint promotes spindle poison-mediated cytotoxicity with distinct kinetics
(2019) Cell Death and Disease
Liu, X. , Chen, Y. , Li, Y.
Targeting mitosis exit: A brake for cancer cell proliferation
(2019) Biochimica et Biophysica Acta - Reviews on Cancer
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