Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes.
Oncotarget
; 6(34): 36063-80, 2015 Nov 03.
Article
em En
| MEDLINE
| ID: mdl-26460824
ABSTRACT
The mechanisms of cancer cell adaptation to the anti-microtubule agents of the taxane family are multifaceted and still poorly understood. Here, in a model of breast cancer cells which display amplified microtubule dynamics to resist Taxol®, we provide evidence that septin filaments containing high levels of SEPT9_i1 bind to microtubules in a way that requires tubulin long chain polyglutamylation. Reciprocally, septin filaments provide a scaffold for elongating and trimming polyglutamylation enzymes to finely tune the glutamate side-chain length on microtubules to an optimal level. We also demonstrate that tubulin retyrosination and/or a high level of tyrosinated tubulin is crucial to allow the interplay between septins and polyglutamylation on microtubules and that together, these modifications result in an enhanced CLIP-170 and MCAK recruitment to microtubules. Finally, the inhibition of tubulin retyrosination, septins, tubulin long chain polyglutamylation or of both CLIP-170 and MCAK allows the restoration of cell sensitivity to taxanes, providing evidence for a new integrated mechanism of resistance.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Ácido Poliglutâmico
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Tubulina (Proteína)
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Neoplasias da Mama
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Paclitaxel
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Septinas
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article