Neuronal-associated microtubule proteins class III beta-tubulin and MAP2c in neuroblastoma: role in resistance to microtubule-targeted drugs.
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 beta-tubulin on the alpha/beta-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 neuroblastoma have been limited. In this study, BE2-C neuroblastoma cells previously selected for resistance to either vincristine (BE/VCR10) or colchicine (BE/CHCb0.2) were found to display significant decreases in neuronal-specific class III beta-tubulin. Interestingly, vincristine-selected cells exhibited increased levels of polymerized tubulin that were not due to alpha-tubulin and class I, II, or III beta-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.
Don
Sima
S
Children's Cancer Institute Australia for Medical Research, High Street, P.O. Box 81, Randwick, New South Wales 2031, Australia.
Verrills
Nicole M
NM
Liaw
Tracy Y E
TY
Liu
Marjorie L M
ML
Norris
Murray D
MD
Haber
Michelle
M
Kavallaris
Maria
M
D019008:Drug Resistance, Neoplasm; D006801:Humans; D008868:Microtubule Proteins / Q000032:analysis / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D050777:Stathmin; D014404:Tubulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C489788:MAP2 protein, human; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C493995:STMN1 protein, human; D050777:Stathmin; D014404:Tubulin; D017239:Paclitaxel