Microtubule-Disrupting Chemotherapeutics Result in Enhanced Proteasome-Mediated Degradation and Disappearance of Tubulin in Neural Cells
Autor: | Dan L. Sackett, Marianne S. Poruchynsky, Lyn M. Huff, Tito Fojo |
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Rok vydání: | 2010 |
Předmět: |
Proteasome Endopeptidase Complex
Cancer Research Vincristine Cell Antineoplastic Agents Microtubules Article Tubulin Microtubule Cell Line Tumor medicine Humans Cytoskeleton Neurons Antibiotics Antineoplastic biology Cell biology medicine.anatomical_structure Oncology Biochemistry Doxorubicin Acetylation Cancer cell Proteasome inhibitor biology.protein DNA Damage medicine.drug |
Zdroj: | Cancer Research. 70:5870-5879 |
ISSN: | 1538-7445 0008-5472 |
Popis: | We sought to examine the effects of microtubule-targeting agents (MTA) on neural cells to better understand the problem of neurotoxicity, their principal side effect, and to possibly develop a model of clinical toxicity. Studies showed that microtubule-depolymerizing agents (MDA) not only disassembled microtubules in neural HCN2 cells but also led to rapid disappearance of tubulin, and that this was specific for MDAs. Tubulin levels decreased to 20% as early as 8 hours after adding vincristine, and to 1% to 30% (mean, 9.8 ± 7.6%; median of 7%) after 100 nmol/L vincristine for 24 hours. This disappearance was reversible. An increase in both glu-terminated and acetylated tubulin, markers of stable tubulin, preceded reaccumulation of soluble tubulin, suggesting a priority for stabilizing tubulin first as microtubules before replenishing the soluble pool. Similar results were shown with other MDAs. Furthermore, microtubule reassembly did not arise from a central focus but instead appeared to involve dispersed nucleation, as evidenced by the appearance of small, stable microtubule stubs throughout the cytoplasm. In contrast, experiments with four nonneural “normal” cell lines and four cancer cell lines resulted in microtubule destabilization but only modest tubulin degradation. Evidence for proteasome-mediated degradation was obtained by demonstrating that adding a proteasome inhibitor before vincristine prevented tubulin disappearance. In summary, MDAs lead to rapid disappearance of tubulin in neural but not in other normal or cancer cells. These results underscore the fine control that occurs in neural cells and may further our understanding of neurotoxicity following MDAs. Cancer Res; 70(14); 5870–9. ©2010 AACR. |
Databáze: | OpenAIRE |
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