Dugina Vera, Vasileva Maria, Khromova Natalia, Vinokurova Svetlana, Shagieva Galina, Mikheeva Ekaterina, Galembikova Aigul, Dunaev Pavel, Kudlay Dmitry, Boichuk Sergei, Kopnin Pavel
A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.
Biological Faculty, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
Int J Mol Sci. 2024 Apr 20;25(8):4530. doi: 10.3390/ijms25084530.
The widespread occurrence of breast cancer and its propensity to develop drug resistance highlight the need for a comprehensive understanding of the molecular mechanisms involved. This study investigates the intricate pathways associated with secondary resistance to taxol in triple-negative breast cancer (TNBC) cells, with a particular focus on the changes observed in the cytoplasmic actin isoforms. By studying a taxol-resistant TNBC cell line, we revealed a shift between actin isoforms towards γ-actin predominance, accompanied by increased motility and invasive properties. This was associated with altered tubulin isotype expression and reorganisation of the microtubule system. In addition, we have shown that taxol-resistant TNBC cells underwent epithelial-to-mesenchymal transition (EMT), as evidenced by Twist1-mediated downregulation of E-cadherin expression and increased nuclear translocation of β-catenin. The RNA profiling analysis revealed that taxol-resistant cells exhibited significantly increased positive regulation of cell migration, hormone response, cell-substrate adhesion, and actin filament-based processes compared with naïve TNBC cells. Notably, taxol-resistant cells exhibited a reduced proliferation rate, which was associated with an increased invasiveness in vitro and in vivo, revealing a complex interplay between proliferative and metastatic potential. This study suggests that prolonged exposure to taxol and acquisition of taxol resistance may lead to pro-metastatic changes in the TNBC cell line.
乳腺癌的广泛发生及其产生耐药性的倾向凸显了全面了解相关分子机制的必要性。本研究调查了三阴性乳腺癌（TNBC）细胞对紫杉醇继发性耐药相关的复杂途径，特别关注细胞质肌动蛋白异构体中观察到的变化。通过研究一种耐紫杉醇的TNBC细胞系，我们发现肌动蛋白异构体之间向以γ-肌动蛋白为主转变，同时细胞运动性和侵袭性增加。这与微管蛋白亚型表达的改变和微管系统的重组有关。此外，我们还表明，耐紫杉醇的TNBC细胞经历了上皮-间质转化（EMT），Twist1介导的E-钙黏蛋白表达下调和β-连环蛋白核转位增加证明了这一点。RNA谱分析显示，与未处理的TNBC细胞相比，耐紫杉醇的细胞在细胞迁移、激素反应、细胞-基质黏附以及基于肌动蛋白丝的过程的正调控方面显著增加。值得注意的是，耐紫杉醇的细胞增殖率降低，这与体外和体内侵袭性增加有关，揭示了增殖潜力和转移潜力之间的复杂相互作用。本研究表明，长期暴露于紫杉醇和获得紫杉醇耐药性可能导致TNBC细胞系发生促转移变化。
