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通过抑制人去势抵抗性前列腺癌PC3细胞中Akt1的表达在体外和体内增强对舒尼替尼的敏感性

Enhanced Sensitivity to Sunitinib by Inhibition of Akt1 Expression in Human Castration-resistant Prostate Cancer PC3 Cells Both In Vitro and In Vivo.

作者信息

Nishikawa Masatomo, Miyake Hideaki, Fujisawa Masato

机构信息

Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.

Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.

出版信息

Urology. 2015 May;85(5):1215.e1-1215.e7. doi: 10.1016/j.urology.2015.02.016.

DOI:10.1016/j.urology.2015.02.016
PMID:25917740
Abstract

OBJECTIVE

To investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castration-resistant prostate cancer PC3 model.

MATERIALS AND METHODS

We initially established PC3 in which the expression vector containing a short hairpin ribonucleic acid targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 after treatment with sunitinib were compared with those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo.

RESULTS

When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying impaired phosphorylation of p44/42 mitogen-activated protein kinase, downregulation of Bcl-2, and upregulation of Bax. In addition, treatment with sunitinib significantly suppressed the migration ability of PC3/sh-Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the significantly marked growth inhibition of PC3/sh-Akt1 compared with that of PC3/C, and apoptotic index in PC3/sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor.

CONCLUSION

Combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with castration-resistant prostate cancer.

摘要

目的

在人去势抵抗性前列腺癌PC3模型中，研究沉默Akt1是否能增强舒尼替尼的抗肿瘤活性。

材料与方法

我们首先构建了导入含靶向Akt1的短发夹核糖核酸表达载体的PC3细胞系（PC3/sh-Akt1）。在体外和体内，将舒尼替尼处理后的PC3/sh-Akt1的各种表型变化与单独转染对照载体的PC3细胞系（PC3/C）进行比较。

结果

在标准培养基中培养时，PC3/sh-Akt1的体外生长与PC3/C几乎相似。然而，与PC3/C相比，PC3/sh-Akt1对舒尼替尼表现出显著更高的敏感性，同时伴有p44/42丝裂原活化蛋白激酶磷酸化受损、Bcl-2下调和Bax上调。此外，与PC3/C相比，舒尼替尼处理显著抑制了PC3/sh-Akt1的迁移能力。在体内，与PC3/C相比，给予舒尼替尼可显著抑制PC3/sh-Akt1的生长，并且舒尼替尼处理的小鼠中PC3/sh-Akt1肿瘤的凋亡指数显著高于PC3/C肿瘤。

结论

Akt1抑制剂与舒尼替尼联合治疗可能是去势抵抗性前列腺癌患者一种有前景的治疗方法。

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