REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer
REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer
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DOI：
10.1038/cgt.2008.58
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发表时间：
2009-01-01
影响因子：
6.4
通讯作者：
Date, H.
中科院分区：
文献类型：
--
作者：
Kawasaki, K.;Watanabe, M.;Date, H.
肿瘤抑制基因Dickkopf-3（Dkk-3）在人前列腺癌和睾丸癌细胞中的过表达可诱导凋亡。本研究的目的是研究REIC/Dkk-3作为乳腺癌治疗靶点的潜力。首先，在乳腺癌细胞系中研究了Ad-REIC处理的体外凋亡作用，因此发现腺病毒介导的REIC/Dkk-3过表达以c-Jun-NH 2-激酶（JNK）磷酸化依赖性方式导致凋亡性细胞死亡。此外，在肿瘤内注射Ad-REIC后，在小鼠模型中观察到体内凋亡效应和MCF/Wt肿瘤生长抑制。由于多药耐药（MDR）是进展期乳腺癌化疗中的主要问题，因此，从多药耐药MCF 7/ADR细胞对阿霉素的敏感性和P-糖蛋白表达的角度研究Ad-REIC治疗的体外效果。Ad-REIC还通过激活JNK下调了MCF 7/ADR细胞P-糖蛋白的表达，并使MCF 7/ADR细胞对阿霉素的耐药性敏感。因此，使用Ad-REIC不仅实现了细胞凋亡诱导，而且实现了抗癌药物抗性的逆转。我们认为REIC/Dkk-3是乳腺癌治疗的一个新靶点，Ad-REIC可能是一种有吸引力的药物，与传统的抗肿瘤药物联合使用。
The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.