Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275 CNRS-Université Côte d'Azur, 660, Route des Lucioles, 06560 Valbonne, France.
Institut de Chimie de Nice (ICN), UMR 7272 CNRS-Université Côte d'Azur, 28, Avenue de Valrose, CEDEX 2, 06108 Nice, France.
Molecules. 2021 Feb 12;26(4):969. doi: 10.3390/molecules26040969.
Breast cancer is a major disease for women worldwide, where mortality is associated with tumour cell dissemination to distant organs. While the number of efficient anticancer therapies increased in the past 20 years, treatments targeting the invasive properties of metastatic tumour cells are still awaited. Various studies analysing invasive breast cancer cell lines have demonstrated that Arf6 is an important player of the migratory and invasive processes. These observations make Arf6 and its regulators potential therapeutic targets. As of today, no drug effective against Arf6 has been identified, with one explanation being that the activation of Arf6 is dependent on the presence of lipid membranes that are rarely included in drug screening. To overcome this issue we have set up a fluorescence-based high throughput screening that follows overtime the activation of Arf6 at the surface of lipid membranes. Using this unique screening assay, we isolated several compounds that affect Arf6 activation, among which the antibiotic chlortetracycline (CTC) appeared to be the most promising. In this report, we describe CTC in vitro biochemical characterization and show that it blocks both the Arf6-stimulated collective migration and cell invasion in a 3D collagen I gel of the invasive breast cancer cell line MDA-MB-231. Thus, CTC appears as a promising hit to target deadly metastatic dissemination and a powerful tool to unravel the molecular mechanisms of Arf6-mediated invasive processes.
乳腺癌是全球女性的主要疾病，其死亡率与肿瘤细胞向远处器官的扩散有关。尽管在过去 20 年中，有效的抗癌疗法数量有所增加，但仍在等待针对转移性肿瘤细胞侵袭特性的治疗方法。各种分析侵袭性乳腺癌细胞系的研究表明，Arf6 是迁移和侵袭过程的重要参与者。这些观察结果使 Arf6 及其调节剂成为潜在的治疗靶点。截至目前，尚未发现有效的针对 Arf6 的药物，其中一个解释是 Arf6 的激活依赖于很少包含在药物筛选中的脂质膜的存在。为了克服这个问题，我们建立了一种基于荧光的高通量筛选方法，该方法可以随着时间的推移跟踪脂质膜表面上 Arf6 的激活。使用这种独特的筛选测定法，我们分离出了几种影响 Arf6 激活的化合物，其中抗生素金霉素（CTC）似乎最有前途。在本报告中，我们描述了 CTC 的体外生化特性，并表明它可以阻断 Arf6 刺激的 MDA-MB-231 侵袭性乳腺癌细胞系在 3D 胶原 I 凝胶中的集体迁移和细胞侵袭。因此，CTC 似乎是一种有前途的针对致命转移性传播的靶点，也是揭示 Arf6 介导的侵袭过程分子机制的有力工具。
