title: Suppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxel.
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.
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal; Centre for Biomedical Research (CBMR), University of Algarve, Faro 8005-139, Portugal; Departamento Ciências Biomédicas e Medicina, University of Algarve, Faro 8005-139, Portugal.
authors.forename: Patrícia M A
authors.initials: PM
authors.lastname: Silva
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal.
authors.forename: Nilza
authors.initials: N
authors.lastname: Ribeiro
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology, FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.affiliation: CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Andrade
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal.
authors.forename: Vânia
authors.initials: V
authors.lastname: Diogo
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Teixeira
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro 8005-139, Portugal; Departamento Ciências Biomédicas e Medicina, University of Algarve, Faro 8005-139, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Florindo
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro 8005-139, Portugal; Departamento Ciências Biomédicas e Medicina, University of Algarve, Faro 8005-139, Portugal.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Tavares
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Porto, Portugal.
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal. Electronic address: hassan.bousbaa@iucs.cespu.pt.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bousbaa
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008940:Mitotic Index; D017239:Paclitaxel / Q000494:pharmacology*; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C549402:SPDL1 protein, human; D050257:Tubulin Modulators; D017239:Paclitaxel
keywords: Apoptosis; Cancer cells; Cell cycle; Paclitaxel; Spindle assembly checkpoint; Spindly