Department of Medical and Clinical Biophysics, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011 Košice, Slovakia.
Institute of Experimental Medicine, Czech Academy of Sciences, Vídeňská 1083, 142 00 Prague, Czech Republic.
Int J Mol Sci. 2023 Jul 12;24(14):11352. doi: 10.3390/ijms241411352.
Breast cancer is the most prevalent cancer type in women worldwide. It proliferates rapidly and can metastasize into farther tissues at any stage due to the gradual invasiveness and motility of the tumor cells. These crucial properties are the outcome of the weakened intercellular adhesion, regulated by small guanosine triphosphatases (GTPases), which hydrolyze to the guanosine diphosphate (GDP)-bound conformation. We investigated the inactivating effect of on Rho GTPases involved signaling pathways after treatment with a high dose of doxorubicin. Label-free quantitative proteomic analysis of the proteome isolated from the MCF-7 breast cancer cell line, treated with 1 μM of doxorubicin, identified , , and GTPases that were inactivated by the protein. Upregulation of the GTPases involved in the transforming growth factor-beta (TGF-beta) signaling pathway initiated epithelial-mesenchymal transitions. These findings demonstrate a key role of the protein in the disruption of the cell adhesion and simultaneously allow for a better understanding of the molecular mechanism of the reduced cell adhesion leading to the subsequent metastasis. The conclusions of this study corroborate the hypothesis that chemotherapy with doxorubicin may increase the risk of metastases in drug-resistant breast cancer cells.
乳腺癌是全球女性最常见的癌症类型。由于肿瘤细胞逐渐侵袭和迁移，它可以在任何阶段迅速扩散并转移到更远的组织。这些关键特性是细胞间黏附力减弱的结果，由小 GTP 酶（GTPases）调节，GTPases 将 GDP 结合构象水解为 GTP。我们研究了在高剂量阿霉素治疗后， 对涉及信号通路的 Rho GTPases 的失活作用。用 1 μM 阿霉素处理 MCF-7 乳腺癌细胞系分离的蛋白质组进行无标记定量蛋白质组学分析，鉴定出 、 、 和 被 蛋白失活的 GTPases。参与转化生长因子-β（TGF-β）信号通路的 GTPases 的上调启动了上皮-间充质转化。这些发现表明 蛋白在破坏细胞黏附中起关键作用，同时更好地理解了导致随后转移的细胞黏附减少的分子机制。本研究的结论证实了这样一种假设，即阿霉素化疗可能会增加耐药性乳腺癌细胞转移的风险。
