Neuronal-associated microtubule proteins class III beta-tubulin and 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 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.

• Authors: Sima Don, Nicole M Verrills, Tracy Y E Liaw, Marjorie L M Liu, Murray D Norris, Michelle Haber, Maria Kavallaris
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 9 Pg. 1137-46 (Sep 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15367708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MAP2 protein, human
• Microtubule Proteins
• Microtubule-Associated Proteins
• Phosphoproteins
• Protein Isoforms
• STMN1 protein, human
• Stathmin
• Tubulin
• Paclitaxel

Topics

• Drug Resistance, Neoplasm
• Humans
• Microtubule Proteins (analysis, metabolism)
• Microtubule-Associated Proteins (analysis, metabolism)
• Microtubules (drug effects, genetics, metabolism)
• Mutation (genetics)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Neurons (immunology, metabolism)
• Paclitaxel (pharmacology)
• Phosphoproteins (analysis, metabolism)
• Protein Isoforms (analysis, metabolism)
• Stathmin
• Tubulin (analysis, genetics, metabolism)
• Tumor Cells, Cultured