Abstract
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.
Highlights
Natural products such as vinblastine and paclitaxel are important anti-tumoral drugs [1]
Since the SKBr3 cells are a model cell line for investigating the role of microtubules in cell migration, we focused our study on this cell line
We observed that in treated cells, many microtubule +ends had lost ch-TOG labeling, but still harbored EB1 comets: there was 25 % less chTOG labeled EB1 comets in eribulin treated cells relative to untreated cells. These results indicate that low doses of eribulin disturbed the recruitment of ch-TOG to microtubule +ends and that the loss of ch-TOG induced a decrease in microtubule growth speed and in microtubule capture, and abrogated directed migration
Summary
Natural products such as vinblastine and paclitaxel are important anti-tumoral drugs [1]. Their mode of action involves primarily the destruction of the microtubule cytoskeleton forming the mitotic spindle, leading to cell cycle arrest in mitosis and to cancer cell death. Survival of cancer patients treated with microtubule targeting agents (MTAs) is frequently limited by tumor resistance to chemotherapies and progression towards invasive and metastatic grades. Detailed characterization of MTA binding to tubulin identified distinct binding pockets, offering alternative opportunities for treatments against tumor resistant to a site-specific class of MTAs [2]. A continuous effort in natural product and medicinal chemistry generated a wealth of MTAs with a diverse array of chemical structures. Eribulin (Halaven ), a synthetic analog of the sponge metabolite halichondrin B [3, www.impactjournals.com/oncotarget
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