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Eribulin targets a ch-TOG-dependent directed migration of cancer cells

Brice Chanez^1,2,3,4, Anthony Gonçalves^1,2,3,4, Ali Badache^1,2,3,4

¹Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France.

|October 27, 2015

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.

Insights

Eribulin, a microtubule targeting agent, disrupts cancer cell migration by affecting microtubule dynamics and depleting key proteins like ch-TOG. This impacts tumor metastasis and angiogenesis.

Area of Science:

Cell Biology
Cancer Research
Pharmacology

Background:

Microtubule targeting agents (MTAs) affect cell migration, potentially impacting tumor metastasis.
Directed cell migration relies on microtubule stabilization at the cell leading edge, controlled by +TIPs.
The precise mechanisms by which MTAs impair cell migration are not fully understood.

Purpose of the Study:

To investigate the effects of eribulin on cancer cell migration and microtubule dynamics.
To elucidate the role of microtubule +end interacting proteins (+TIPs) in eribulin's mechanism of action.

Main Methods:

Utilized eribulin, a novel MTA, to treat cancer cells.
Assessed changes in microtubule growth speed, cortical stabilization, and directed cell migration.
Quantified the levels and localization of +TIPs, including EB1, CLIP-170, and ch-TOG.
Performed knockdown experiments for ch-TOG.

Main Results:

Eribulin decreased microtubule growth speed, impaired cortical stabilization, and inhibited directed migration.
Eribulin caused a dose-dependent depletion of EB1, CLIP-170, and ch-TOG from microtubule +ends.
Disruption of ch-TOG localization by eribulin impacted microtubule dynamics and migration, similar to ch-TOG knockdown effects.

Conclusions:

Eribulin's interaction with microtubule tips leads to ch-TOG loss, altering microtubule dynamics.
This alteration in microtubule dynamics inhibits cancer cell migration.
The findings suggest a novel mechanism for eribulin's anti-migratory effects relevant to cancer metastasis.

Read full analysis

Keywords:

EB1 ch-TOG eribulin microtubule migration

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