Eribulin targets a ch-TOG-dependent directed migration of cancer cells.
Non-cytotoxic concentrations of microtubule targeting agents (MTAs) interfere with the dynamics of interphase microtubules and affect cell migration, which could impair tumor angiogenesis and metastasis. The underlying mechanisms however are still ill-defined. We previously established that directed cell migration is dependent on stabilization of microtubules at the cell leading edge, which is controlled by microtubule +end interacting proteins (+TIPs). In the present study, we found that eribulin, a recently approved MTA interacting with a new class of binding site on β-tubulin, decreased microtubule growth speed, impaired their cortical stabilization and prevented directed migration of cancer cells. These effects were reminiscent of those observed when +TIP expression or cortical localization was altered. Actually, eribulin induced a dose-dependent depletion of EB1, CLIP-170 and the tubulin polymerase ch-TOG from microtubule +ends. Interestingly, eribulin doses that disturbed ch-TOG localization without significant effect on EB1 and CLIP-170 comets, had an impact on microtubule dynamics and directed migration. Moreover, knockdown of ch-TOG led to a similar inhibition of microtubule growth speed, microtubule capture and chemotaxis. Our data suggest that eribulin binding to the tip of microtubules and subsequent loss of ch-TOG is a priming event leading to alterations in microtubule dynamics and cancer cell migration.
Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, Marseille, France.|CNRS, UMR7258, F-13009, Marseille, France.
Brice
B
Chanez
Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, Marseille, France.|CNRS, UMR7258, F-13009, Marseille, France.
Anthony
A
Gonçalves
Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, Marseille, France.|CNRS, UMR7258, F-13009, Marseille, France.
Ali
A
Badache
Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix-Marseille Université, Marseille, France.|CNRS, UMR7258, F-13009, Marseille, France.
Pascal
P
Verdier-Pinard
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000378:metabolism / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology*; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D050257:Tubulin Modulators; C454180:CKAP5 protein, human; C490954:eribulin; D000095662:Polyether Polyketides
EB1; ch-TOG; eribulin; microtubule; migration