RPN2 gene confers docetaxel resistance in breast cancer
RPN2 gene confers docetaxel resistance in breast cancer
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DOI：
10.1038/nm.1858
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发表时间：
2008-09-01
期刊：
影响因子：
82.9
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
--
作者：
Honma, Kimi;Iwao-Koizumi, Kyoko;Ochiya, Takahiro
癌细胞获得的耐药性已导致治疗失败。为了了解乳腺癌细胞对多西紫杉醇耐药的调控网络，并确定治疗的分子靶点，我们针对36个基因进行了小干扰RNA(SiRNAs)测试，这些基因在对多西紫杉醇无反应者中表达升高，以了解是否有能力促进耐多西紫杉醇的人乳腺癌细胞(MCF7-ADR细胞)的凋亡。结果表明，在多西紫杉醇存在下，核糖蛋白II(RPN2)编码基因的下调最有效地诱导了MCF7-ADR细胞的凋亡。RPN2沉默导致P-糖蛋白糖基化减少，膜定位降低，从而使MCF7-ADR细胞对多西紫杉醇敏感。此外，在两种耐药模型中，体内注射针对RPN2的siRNA显著减少了肿瘤的生长。因此，RPN2沉默使癌细胞对多西紫杉醇产生超敏反应，RPN2可能成为基于RNA干扰的耐药治疗的新靶点。
Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribopholin II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.