Oncotarget

Research Papers:

Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes

Laurence Froidevaux-Klipfel _, Benjamin Targa, Isabelle Cantaloube, Hayat Ahmed-Zaïd, Christian Poüs and Anita Baillet

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Oncotarget. 2015; 6:36063-36080. https://doi.org/10.18632/oncotarget.5373

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Abstract

Laurence Froidevaux-Klipfel1,*, Benjamin Targa1, Isabelle Cantaloube1, Hayat Ahmed-Zaïd1, Christian Poüs1,2, Anita Baillet1

1INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France

2Laboratoire de Biochimie-Hormonologie, Hôpital Antoine Béclère, AP-HP, Clamart, France

*Present address: UMR 996, “Inflammation, chimiokines et immunopathologie,” INSERM, Université Paris-Saclay, 92140 Clamart, France

Correspondence to:

Anita Baillet, e-mail: anita.baillet@u-psud.fr

Keywords: septin, microtubule polyglutamylation, Taxol® resistance, tyrosinated tubulin

Received: June 29, 2015     Accepted: September 25, 2015     Published: October 07, 2015

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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