Falsey Ryan R, Marron Marilyn T, Gunaherath G M Kamal B, Shirahatti Nikhil, Mahadevan Daruka, Gunatilaka A A Leslie, Whitesell Luke
Nat Chem Biol. 2006 Jan;2(1):33-8. doi: 10.1038/nchembio755. Epub 2005 Dec 11.
The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter protein annexin II. We now report that the compound withaferin A (1) can alter cytoskeletal architecture in a previously unknown manner by covalently binding annexin II and stimulating its basal F-actin cross-linking activity. Drug-mediated disruption of F-actin organization is dependent on annexin II expression by cells and markedly limits their migratory and invasive capabilities at subcytotoxic concentrations. Given the extensive ethnobotanical history of withaferin-containing plant preparations in the treatment of cancer and inflammatory and neurological disorders, we suggest that annexin II represents a feasible, previously unexploited target for therapeutic intervention by small-molecule drugs.
肌动蛋白细胞骨架支持多种细胞过程，如内吞作用、定向生长、黏附及迁移。然而，细胞骨架的动态特性使得界定众多调节肌动蛋白组织的辅助分子的作用变得困难，尤其是多功能衔接蛋白膜联蛋白II。我们现在报告，化合物睡茄内酯A（1）可通过共价结合膜联蛋白II并刺激其基础F-肌动蛋白交联活性，以一种前所未知的方式改变细胞骨架结构。药物介导的F-肌动蛋白组织破坏取决于细胞中膜联蛋白II的表达，并且在亚细胞毒性浓度下显著限制其迁移和侵袭能力。鉴于含睡茄内酯的植物制剂在治疗癌症、炎症和神经系统疾病方面有着广泛的民族植物学应用历史，我们认为膜联蛋白II是小分子药物进行治疗干预的一个可行的、此前未被开发的靶点。
