Lower Tubulin Expression in Glioblastoma Stem Cells Attenuates Efficacy of Microtubule-Targeting Agents

Abstract

Sensitivity to microtubule-targeting agents (MTAs) varies among cancers and predicting the response of individual cancer patients to MTAs remains challenging. As microtubules possess vast molecular heterogeneity generated by tubulin isotypes and their post-translational modifications, we questioned whether this heterogeneity can impact MTA sensitivity. We investigated microtubule heterogeneity in 15 glioblastoma cell lines and measured sensitivity of orthogonal MTAs using a per-division growth rate inhibition method that corrects for the confounding effects of variable cell proliferation rates. We found that the tubulin profile is unique for each glioblastoma cell line and that the total α- and β-tubulin levels impact on MTA sensitivity. The baseline levels of α- and β-tubulin were up to 20% lower in cells that were not effectively killed by MTAs. We report that lower α/β-tubulin expression is associated with lack of cell differentiation and increased expression of stemness markers. The dedifferentiated stem-like cells with low α/β-tubulin levels survive MTAs treatment via reversible nonmutational dormancy. Our findings provide novel insights into the relationships between microtubules and MTAs and lay a foundation for better understanding of the sensitivity of cancer cells to MTAs.