Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity
Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity
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DOI：
10.1002/pros.20783
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发表时间：
2008-09-01
期刊：
影响因子：
2.8
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
--
作者：
Hayashi, Norihiro;Koller, Erich;Gleave, Martin E.
目标。微管抑制剂，包括多西紫杉醇，是许多癌症的活性细胞毒，包括前列腺癌（CaP）。Eg5基因是激酶5家族的一员，在正常的有丝分裂纺锤体功能中起着关键作用，是癌细胞增殖的潜在微管相关靶点。为了研究Eg5在CaP中的功能活性，我们采用了一种靶向Eg5的反义寡核苷酸（ASO），在体外和体内研究了Eg5 ASO对雄激素非依赖性CaP细胞的效力和抗癌活性。与LNCa P细胞相比，PC3细胞表达更高的Eg5蛋白和RNA水平。在两种细胞系中，Eg5 ASO处理以剂量依赖的方式降低mRNA和蛋白水平，并在100 nM处观察到Eg5蛋白水平完全降低。使用Eg5 ASO还观察到对细胞生长的剂量依赖性抑制，有效的G2/M期阻滞和亚g1期凋亡部分的增加。令人惊讶的是，低剂量Eg5 ASO显著拮抗紫杉醇的细胞毒作用。在体内，Eg5 ASO单药治疗显著降低LNCaP和PC-3肿瘤的生长，但与紫杉醇联合治疗没有产生额外的益处。这些发现表明，虽然Eg5是延迟雄激素非依赖性CaP生长的潜在靶点，但与紫杉醇联合治疗可能并不理想。
OBJECTIVES. Microtubular inhibitors, including docetaxel, are active cytotoxics in many cancers, including prostate cancer (CaP). The Eg5 gene, a member of the kinesin-5 family, plays critical roles in proper mitotic spindle function, and is a potential microtubule-related target for proliferating cancer cells. To investigate the functional activities of Eg5 in CaP, we used an antisense oligonucleotide (ASO) targeting Eg5 to assess the potency and anti-cancer activity of Eg5 ASO treatment for androgen-independent CaP cells in vitro and in vivo.RESULTS. PC3 cells express higher Eg5 protein and in RNA levels compared to LNCa P cells. In both cell lines, Eg5 ASO treatment reduced mRNA and protein levels in a dose-dependent manner and a complete reduction of Eg5 protein levels was observed at 100 nM. Dose-dependent inhibition in cell growth, potent G2/M phase arrest, and increases in apoptotic sub-G1 fraction were also observed using Eg5 ASO. Surprisingly, low dose Eg5 ASO significantly antagonized cytotoxic effects of paclitaxel. In vivo, Eg5 ASO monotherapy significantly reduced both LNCaP and PC-3 tumor growth but combination treatment with paclitaxel did not yield additive benefits.CONCLUSIONS. These findings suggest that while Eg5 is a potential target to delay androgen-independent CaP growth, combination treatment with paclitaxel may not be desirable.