Bijman Marcel N A, van Berkel Maria P A, van Nieuw Amerongen Geerten P, Boven Epie
Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Biochem Pharmacol. 2008 Sep 15;76(6):707-16. doi: 10.1016/j.bcp.2008.06.014. Epub 2008 Jul 2.
Cellular movement is mainly orchestrated by the actin and microtubule cytoskeleton in which Rho GTPases closely collaborate. We studied whether cytoskeleton-interfering agents at subtoxic and 50% growth-inhibiting concentrations affect motility of five unselected human ovarian cancer cell lines. Cisplatin and doxorubicin as control cytotoxic agents were not effective, the microtubule-targeting agents docetaxel, epothilone B and vinblastine only marginally inhibited cell motility, while the actin-targeting agent cytochalasin D was most potent in hampering both cell migration and invasion. Disturbance of microtubule dynamics by docetaxel did not importantly affect the cellular structures of beta-tubulin and F-actin. In contrast, hindrance of actin dynamics by cytochalasin D resulted in loss of lamellipodial extensions, induced thick layers of F-actin and disorder in cellular organization. In OVCAR-3 cells the activity of Rac1 was only slightly diminished by docetaxel, but clearly reduced by cytochalasin D. In conclusion, targeting the actin cytoskeleton might provide a means to prevent metastasis formation.
细胞运动主要由肌动蛋白和微管细胞骨架协调完成，其中Rho GTP酶密切协作。我们研究了亚毒性和50%生长抑制浓度的细胞骨架干扰剂是否会影响5种未经挑选的人卵巢癌细胞系的运动性。作为对照的细胞毒性药物顺铂和阿霉素无效，靶向微管的药物多西他赛、埃坡霉素B和长春碱仅对细胞运动有轻微抑制作用，而靶向肌动蛋白的药物细胞松弛素D在阻碍细胞迁移和侵袭方面最为有效。多西他赛对微管动力学的干扰对β-微管蛋白和F-肌动蛋白的细胞结构没有重要影响。相反，细胞松弛素D对肌动蛋白动力学的阻碍导致片状伪足延伸消失，诱导F-肌动蛋白形成厚层并使细胞组织紊乱。在OVCAR-3细胞中，多西他赛仅轻微降低Rac1的活性，但细胞松弛素D明显降低其活性。总之，靶向肌动蛋白细胞骨架可能是预防转移形成的一种方法。
