1] Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA [2] Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
Cancer Gene Ther. 2013 Nov;20(11):630-7. doi: 10.1038/cgt.2013.58. Epub 2013 Oct 25.
RhoA and its downstream effector Rho-associated coiled-coil-forming kinase (ROCK) are known regulators of the formation of actin cytoskeleton in cells. Actin cytoskeleton is involved in paramyxovirus infection; we, therefore, examined the effect of ROCK inhibition on measles virus (MV) cytopathic effect and replication. Treatment with the ROCK inhibitor, Y27632, significantly increased syncytia size in tumor cell lines following MV infection, associated with cytoskeleton disruption as demonstrated by actin staining. Treatment of prostate cancer, breast cancer and glioblastoma tumor cell lines with Y27632 following MV infection resulted in increased cytopathic effect, as assessed by trypan blue exclusion assays. In addition, there was a significant increase in viral proliferation by at least one log or more as tested in one-step viral growth curves. Increased viral replication was also observed in athymic nude mice bearing MDA-MB-231 xenografts following combination treatment with MV and Y27632. In summary, inhibition of the ROCK kinase by Y27632 enhanced the oncolytic effect of MV and viral proliferation; this approach merits further translational investigation.
RhoA 及其下游效应物 Rho 相关卷曲螺旋形成激酶（ROCK）是细胞中肌动蛋白细胞骨架形成的已知调节剂。肌动蛋白细胞骨架参与副粘病毒感染；因此，我们研究了 ROCK 抑制对麻疹病毒（MV）致细胞病变效应和复制的影响。ROCK 抑制剂 Y27632 处理后，MV 感染的肿瘤细胞系中的合胞体大小显著增加，细胞骨架破坏，如肌动蛋白染色所示。MV 感染后，用 Y27632 处理前列腺癌、乳腺癌和神经胶质瘤肿瘤细胞系，通过台盼蓝排除试验评估，致细胞病变效应增加。此外，通过一步法病毒生长曲线测试，病毒增殖至少增加了一个对数级。在接受 MV 和 Y27632 联合治疗的携带 MDA-MB-231 异种移植物的裸鼠中，也观察到病毒复制增加。总之，Y27632 抑制 ROCK 激酶增强了 MV 的溶瘤作用和病毒增殖；这种方法值得进一步的转化研究。
