title: Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes.
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.
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.|Present address: UMR 996, "Inflammation, Chimiokines et Immunopathologie," INSERM, Université Paris-Saclay, Clamart, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Froidevaux-Klipfel
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Targa
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cantaloube
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Hayat
authors.initials: H
authors.lastname: Ahmed-Zaïd
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.|Laboratoire de Biochimie-Hormonologie, Hôpital Antoine Béclère, AP-HP, Clamart, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Poüs
authors.affiliation: INSERM, UMR-S-1193, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Baillet
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011099:Polyglutamic Acid / Q000378:metabolism*; D058112:Septins / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D014404:Tubulin; D011099:Polyglutamic Acid; D058112:Septins; D017239:Paclitaxel
keywords: Taxol® resistance; microtubule polyglutamylation; septin; tyrosinated tubulin