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Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
Published on: May 14, 2018
Paclitaxel-dependent cell lines reveal a novel drug activity
Anutosh Ganguly1, Hailing Yang, Fernando Cabral
1Department of Integrative Biology and Pharmacology, The University of Texas Medical School, 6431 Fannin St., Houston, TX 77030, USA.
Abstract:
We previously described the isolation of Tax 18 and Tax 11-6, two paclitaxel-dependent cell lines that assemble low amounts of microtubule polymer and require the drug for cell division. In the present studies, fluorescence time-lapse microscopy was used to measure microtubule dynamic instability behavior in these cells. The mutations were found to cause small decreases in microtubule growth and shortening, but the changes seemed unable to explain the defects in microtubule polymer levels or cell division. Moreover, paclitaxel further suppressed microtubule dynamics at low drug concentrations that were insufficient to rescue the mutant phenotype. Wild-type (WT) cells treated with similar low drug concentrations also had highly suppressed microtubules, yet experienced no problems with cell division. Thus, the effects of paclitaxel on microtubule dynamics seemed to be unrelated to cell division in both WT and mutant cell lines. The higher drug concentrations needed to rescue the mutant phenotype instead inhibited the formation of unstable microtubule fragments that appeared at high frequency in the drug-dependent, but not WT, cell lines. Live cell imaging revealed that the fragments were generated by microtubule detachment from centrosomes, a process that was reversed by paclitaxel. We conclude that paclitaxel rescues mutant cell division by inhibiting the detachment of microtubule minus ends from centrosomes rather than by altering plus-end microtubule dynamics.
Insights
Paclitaxel rescues cell division in drug-dependent cell lines by preventing microtubule detachment from centrosomes. This mechanism, rather than altering microtubule dynamics, is key to restoring normal cell function.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Two paclitaxel-dependent cell lines, Tax 18 and Tax 11-6, exhibit low microtubule polymer levels and require paclitaxel for cell division.
- Previous studies identified these cell lines but did not fully elucidate the mechanism of paclitaxel's rescue effect.
Purpose of the Study:
- To investigate the role of microtubule dynamic instability in paclitaxel-dependent cell lines.
- To determine how paclitaxel rescues the cell division defects in these mutant cell lines.
Main Methods:
- Utilized fluorescence time-lapse microscopy to analyze microtubule dynamic instability in wild-type and mutant cells.
- Quantified microtubule growth, shortening, and fragment formation under varying paclitaxel concentrations.
- Observed microtubule minus-end detachment from centrosomes using live cell imaging.
Main Results:
- Mutations in Tax 18 and Tax 11-6 caused minor alterations in microtubule growth and shortening, insufficient to explain observed defects.
- Low paclitaxel concentrations suppressed microtubule dynamics in both mutant and wild-type cells without rescuing mutant phenotype.
- Paclitaxel rescued mutant cell division by inhibiting the formation of unstable microtubule fragments, which originated from centrosome detachment.
Conclusions:
- Paclitaxel's rescue of mutant cell division is primarily mediated by inhibiting microtubule minus-end detachment from centrosomes.
- The drug's effect on microtubule dynamics at the plus-end appears unrelated to its role in rescuing cell division in these specific cell lines.
- This study reveals a novel mechanism for paclitaxel's action, focusing on microtubule-centrosome interactions rather than solely on dynamic instability.
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