Abstract
Overexpression of Tau protein in breast cancer cells is identified as an indicator for potential resistance to taxane-based therapy. As reported findings have been obtained mostly from clinical studies, the undetermined underlying mechanism of such drug resistance needs to be thoroughly explored through comprehensive in vitro evaluations. Tau and Taxol bind to the beta tubulin site in microtubules’ structure. This is of particular interest in breast cancer, as microtubules of these cancer cells are structurally distinct from some other microtubules, such as neuronal microtubules, due to their unique beta tubulin isotype distribution. The observed changes in the in vitro polymerization of breast cancer microtubules, and the different function of some molecular motors along them, leave open the possibility that the drug resistance mechanism can potentially be associated with different responses of these microtubules to Tau and Taxol. We carried out a series of parallel experiments to allow comparison of the in vitro dual effect of Tau and Taxol on the polymerization of MCF7 microtubules. We observed a concentration-dependent demotion-like alteration in the self-polymerization kinetics of Tau-induced MCF7 microtubules. In contrast, microtubules polymerized under the simultaneous effects of Tau and Taxol showed promoted assembly as compared with those observed in Tau-induced microtubules. The analysis of our data obtained from the length of MCF7 microtubules polymerized under the interaction with Tau and Taxol in vitro suggests that the phenomenon known as drug resistance in microtubule-targeted drugs such as Taxol may not be directly linked to the different responses of microtubules to the drug. The effect of the drug may be mitigated due to the simultaneous interactions with other microtubule-associated proteins such as Tau protein. The observed regulatory effect of Tau and Taxol on the polymerization of breast cancer microtubules in vitro points to additional evidence for the possible role of tubulin isotypes in microtubules’ functions.
Highlights
Microtubules (MTs), one of the intracellular filaments, contribute to diverse cellular functions including cell division, cell shape, and intracellular transportation
Motivated by the need to more clearly understand the complexity of drug resistance in breast cancer cells and possible underlying mechanisms, we studied the effect of the dual interaction of Tau and Taxol on the assembly and polymerization of MCF7 microtubules in vitro through comparing the length of MCF7 microtubules in parallel experiments
We developed a dark-field video microscopy method to visualize and analyze the assembly of individual breast cancer microtubules under the dual effect of Tau protein and Taxol
Summary
Microtubules (MTs), one of the intracellular filaments, contribute to diverse cellular functions including cell division, cell shape, and intracellular transportation. These dynamic bio-filaments are structured from α- and β-tubulin heterodimers. In vitro studies on the interaction of Tau protein with neuronal microtubules showed that Tau protein promotes the polymerization and stabilization of neuronal microtubules [9,10,11]. Among these extensive studies, a study by Panda et al reported the regulatory effect of Tau protein on the dynamics of neuronal microtubules in vitro by thoroughly evaluating the role which different isoforms of Tau protein can play in altering microtubules’ dynamics. The presence of different isoforms of Tau protein in non-neuronal cells has been observed, which, together with the study by Panda et al, supports a relationship between the source of Tau protein and its regulatory role in microtubules [13]
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