Abstract
Paclitaxel has been reported to inhibit cell division by suppressing microtubule dynamics at low concentrations that do not alter microtubule polymer levels. Although our studies confirm that paclitaxel suppresses microtubule dynamics at low concentrations, we show that suppression of dynamics is insufficient to inhibit cell proliferation. Wild-type CHO cells exhibited a dose-dependent decrease in microtubule dynamicity that reached a minimum at concentrations that had no observable effect on the ability of the cells to divide. Moreover, paclitaxel-dependent mutant cells that assemble reduced amounts of microtubule polymer and require paclitaxel for proliferation, exhibited a similar dose response for suppression of dynamics but much higher drug concentrations were needed to restore cell division. Thus, maximal suppression of microtubule dynamics neither inhibited the proliferation of wild-type cells, nor rescued cell division in paclitaxel-dependent cells. Instead, the higher concentrations of drug needed to restore mutant cell division caused the disappearance of microtubule fragments commonly seen in these cell lines. Using live cell imaging, we found that microtubule fragments are generated by detachment from microtubule organizing centers, and that paclitaxel acts to prevent this detachment, thereby raising microtubule polymer levels. We conclude that low paclitaxel concentrations act at microtubule plus ends to inhibit dynamics, but that higher concentrations are needed to inhibit cell division and prevent microtubule detachment from organizing centers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-53.
- ©2010 American Association for Cancer Research
Volume 70, Issue 8 Supplement
