RhoA/ROCK pathway inhibition by fasudil suppresses the vasculogenic mimicry of U2OS osteosarcoma cells in vitro
| Autor: | Zhenyu Li, Ji-Quan Fan, Gang Wu, Xian-Yi Cai, Fang Zhu, Liling Zhang, Yun Xia, Jinghua Ren |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research RHOA Angiogenesis Cell Plasticity Fluorescent Antibody Technique Bone Neoplasms Biology 03 medical and health sciences 0302 clinical medicine Cell Movement 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Cell Line Tumor Humans Pharmacology (medical) ROCK1 Vasculogenic mimicry Protein Kinase Inhibitors Cytoskeleton Cell Proliferation Pharmacology Matrigel Osteosarcoma rho-Associated Kinases Neovascularization Pathologic Kinase Fasudil Cell biology 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Signal transduction rhoA GTP-Binding Protein Signal Transduction |
| Zdroj: | Anti-cancer drugs. 28(5) |
| ISSN: | 1473-5741 |
| Popis: | GTPase RhoA and its downstream Rho-associated coiled-coil-containing protein kinases (ROCKs) are frequently overexpressed in human cancers. Inhibition of the RhoA/ROCK pathway blocks angiogenesis mediated by the vascular endothelial growth factor, which led us to investigate the role of this pathway in vasculogenic mimicry (VM) - a process by which aggressive cancer cells form vessel-like structures that provide adequate blood supply for tumor growth. We showed that the expression of RhoA and its effector kinases ROCK1/2 was much higher in human osteosarcoma (OS) tissues and the human OS cell line U2OS than in nontumorous tissues and cell line hFOB 1.19 using western blot analysis and real-time PCR. Inhibition of the RhoA/ROCK signaling pathway by the pharmacological inhibitor fasudil reduced vascular-like channels of U2OS cells in Matrigel. Furthermore, we used rhodamine-phalloidin immunofluorescence, wound healing assay, and transwell migration assay to examine the effect of fasudil on tumor cell plasticity and motility, both of which play key roles in VM formation. Finally, we explored the underlying mechanisms of fasudil-induced VM destruction. In this context, we showed that the RhoA/ROCK signaling pathway is a novel regulator in VM of U2OS OS cells and suggest that fasudil in conjunction with established treatments may present a novel therapeutic strategy for OS. |
| Databáze: | OpenAIRE |
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