Eliminação da Spindly: um gatilho para o suicídio de células cancerígenas

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Eliminação da Spindly: um gatilho para o suicídio de células cancerígenas

Quarta, 10.05.2017

Um estudo liderado por investigadores da CESPU, Patrícia Silva e Hassan Bousbaa, publicado na prestigiosa revista “Cancer Letters” de 28 de maio de 2017, revela que a eliminação seletiva da Spindly, uma proteína necessária para a divisão correta das células normais, obriga as células cancerígenas tratadas por agentes quimioterápicos clássicos, a suicidar-se. Esta estratégia poderá ser um auxílio valioso aos agentes clássicos, como o paclitaxel, no combate ao cancro. O estudo contou com a colaboração de um grupo de investigação do IPATIMUP/i3S, liderado por Helena Vasconcelos, e da Universidade do Algarve, liderado por Álvaro Tavares.


Patrícia M.A. Silva a,b,c Nilza Ribeiro a, Raquel T. Lima d,e,f, Claudia Andrade g Vania Diogo a, Joana Teixeira a, Claudia Florindo b,c, Álvaro Tavares b,c, M. Helena Vasconcelos d,e,h and Hassan Bousbaa a,i

a 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

b Centre for Biomedical Research (CBMR), University of Algarve, Faro 8005-139, Portugal

c Departamento Ciências Biomédicas e Medicina, University of Algarve, Faro 8005-139, Portugal

d i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Porto, Portugal

e Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Portugal

f Department of Pathology, FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal

g CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Medicas, Universidade NOVA de Lisboa, Lisboa, Portugal

h Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Porto, Portugal

i Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal


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.

Cancer Letters

http://www.sciencedirect.com/science/article/pii/S0304383517301337