Department of Physics, Seton Hall University, South Orange, NJ 07079, USA.
Int J Mol Sci. 2022 Jan 8;23(2):677. doi: 10.3390/ijms23020677.
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.
在乳腺癌细胞中过度表达 Tau 蛋白被鉴定为对紫杉烷类药物治疗产生潜在耐药性的指标。由于这些发现主要来自临床研究，因此需要通过全面的体外评估来深入探讨这种耐药性的潜在机制。Tau 和 Taxol 与微管结构中β微管蛋白结合。这在乳腺癌中尤为重要，因为这些癌细胞的微管由于其独特的β微管蛋白同工型分布，与其他微管（如神经元微管）在结构上有所不同。观察到乳腺癌微管体外聚合的变化，以及它们沿微管的一些分子马达的不同功能，这表明耐药机制可能与这些微管对 Tau 和 Taxol 的不同反应有关。我们进行了一系列平行实验，以比较 Tau 和 Taxol 对 MCF7 微管聚合的体外双重作用。我们观察到 Tau 诱导的 MCF7 微管的自聚合动力学呈浓度依赖性的解聚样改变。相比之下，同时存在 Tau 和 Taxol 作用下聚合的微管与 Tau 诱导的微管相比，组装得到促进。从 Tau 和 Taxol 体外相互作用诱导 MCF7 微管聚合的长度获得的数据分析表明，在微管靶向药物（如 Taxol）中观察到的耐药现象可能与微管对药物的不同反应直接相关。由于与其他微管相关蛋白（如 Tau 蛋白）的同时相互作用，药物的作用可能会减弱。Tau 和 Taxol 对体外乳腺癌微管聚合的观察调节作用进一步证明了微管蛋白同工型在微管功能中的可能作用。
