Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo
Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo
复制标题
Rho 激酶抑制剂法舒地尔在体外和体内抑制胶质母细胞瘤细胞系的进展
DOI：
10.4161/cbt.9.11.11634
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发表时间：
2010-06-01
影响因子：
3.6
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Deng, Lin;Li, Gang;Zhang, Jian
越来越多的证据表明，Rho/Rho激酶（ROCK）信号通路在肿瘤中上调，并在癌症侵袭和增殖中发挥关键作用。本研究的目的是探讨Rho/ROCK抑制剂法舒地尔的抗肿瘤作用，包括体外和体内抑制胶质母细胞瘤（GBM）细胞系进展的可能机制。用不同浓度的法舒地尔、Y27632和ROCK siRNA处理T98 G和U251细胞后，检测ROCK抑制剂对培养的肿瘤细胞的迁移、侵袭、侵袭相关基因表达、增殖和凋亡的影响。结果表明，法舒地尔能显著抑制成纤维细胞的增殖、迁移和侵袭能力（P < 0.05），并能抑制成纤维细胞基质金属蛋白酶-2（MMP-2）的mRNA和蛋白表达，且呈剂量依赖性。此外，法舒地尔处理导致T98 G和U251中细胞凋亡的剂量依赖性增加。建立颅内异种移植瘤模型。肿瘤冰冻切片及各组小鼠存活时间表明法舒地尔在体内可抑制胶质瘤的侵袭和生长。基于这些结果，法舒地尔通过抑制ROCK在体外和体内抑制GBM的进展。这可能与降低MMP-2表达和诱导肿瘤细胞凋亡有关。Rho/ROCK信号通路可能成为抗肿瘤治疗的一个有前途的靶点。法舒地尔可能是治疗GBM的一种有吸引力的抗肿瘤候选药物。
There is growing evidence that the Rho/Rho-kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and proliferation. The aim of this study was to explore the anti-tumor effects of Rho/ROCK inhibitor, fasudil, including the possible mechanisms involved in the suppression of the glioblastoma (GBM) cell line progression in vitro and in vivo. After T98G and U251 cells were treated with various concentrations of fasudil, Y27632, and ROCK siRNA, the effects of ROCK inhibitors on migration, invasion, invasion-related gene expressions, proliferation, and apoptosis of cultured tumor cells were examined. The results indicated that fasudil significantly inhibited not only proliferation, migration, and invasiveness (P < 0.05) but also the mRNA and protein expressions of matrix metalloproteinase-2 (MMP-2) in a dose-dependent manner. Moreover, fasudil treatment resulted in a dose-dependent increase of apoptosis in T98G and U251. The intracranial xenograft models were established. The cryosection of the tumor and the survival time of mice in each group indicated that fasudil could inhibit glioma invasion and growth in vivo. Based on the results, fasudil suppresses the progression of GBM in vitro and in vivo by inhibiting ROCK. This could be linked to the decreased MMP-2 expression and the induction of apoptosis in tumor cells. The Rho/ROCK signaling pathway may prove to be a promising target in anti-tumor therapy. Fasudil may be an attractive anti-tumor drug candidate for the treatment of GBM.