Neuronal-associated microtubule proteins class III β-tubulin ad MAP2c in neuroblastoma: Role in resistance to microtubule-targeted drugs

Abstract

Advanced stage neuroblastoma has a poor clinical outcome and microtubule-destabilizing agents, such as the Vinca alkaloids, are an important component in the treatment of this childhood cancer. Vinca alkaloids bind to β-tubulin on the α/β-tubulin heterodimer and disrupt microtubule dynamics, leading to cell death. To date, studies examining the contribution of microtubules and associated proteins to the efficacy of microtubule-destabilizing agents in neuroblastorna have been limited. In this study, BE(2)-C neuroblastoma cells previously selected for resistance to either vincristine (BE/VCR10 or colchicine (BE/CHCbO.2) were found to display significant decreases in neuronal-specific class III β-tubulin. Interestingly, vincristine-selected cells exhibited increased levels of polymerized tubulin that were not due to α-tubulin and class I, II, or III β-tubulin mutations. Expression levels of the microtubule-depolymerizing protein stathmin were significantly increased in BE/VCR10 cells. In contrast, levels of MAP2a and MAP2b were relatively unaltered. A marked decrease in the neuronal protein, MAP2c, was identified in the vincristine-selected cells and, to a lesser extent, in the colchicine-selected cells. This is the first report describing specific microtubule alterations in neuroblastoma cells resistant to tubulin-targeted agents. The results indicate a need to identify the factors responsible for resistance to tubulin-targeted agents in neuroblastoma so that improved and novel treatment strategies can be developed for this drug refractory disease. Copyright © 2004 American Association for Cancer Research.