Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells.
Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells.
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DOI：
10.4161/cc.8.19.9751
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发表时间：
2009-10-01
期刊：
影响因子：
--
通讯作者：
Wu GS
中科院分区：
文献类型：
--
作者：
Wang J;Zhou JY;Zhang L;Wu GS
虽然顺铂是一种非常有效的抗癌剂，对几种类型的癌症，包括卵巢癌，获得性耐药的机制还没有完全了解。通过顺铂长期暴露于卵巢癌细胞系，我们建立了两个顺铂耐药细胞系OV 433和tOV 112 D。我们的研究结果表明，其顺铂耐药的机制是不同的。在OV 433细胞中，顺铂耐药与丝裂原活化蛋白激酶（MAPK）磷酸酶-1（MKP-1）表达增加相关。通过siRNA敲低MKP-1表达或雷公藤内酯醇抑制MKP-1表达，顺铂耐药的OV 433细胞变得对顺铂敏感，随后增加顺铂诱导的凋亡。另一方面，在tOV 112 D细胞中，获得性顺铂抗性与Bcl-2蛋白水平的增加相关。通过药物抑制剂棉酚抑制Bcl-2蛋白的活性或通过siRNA敲低Bcl-2的表达，顺铂耐药tOV 112 D细胞变得对顺铂敏感，随后增加顺铂诱导的凋亡。因此，我们的数据表明，获得性顺铂耐药的机制在卵巢癌细胞中是不同的，这涉及与细胞存活途径相关的分子的上调。
Although cisplatin is a very effective anticancer agent against several types of cancer including ovarian cancer, the mechanisms of acquired resistance are not fully understood. By chronically exposing cisplatin to ovarian cancer cell lines, we established two cisplatin-resistant cell lines OV433 and tOV112D. Our results indicate that the mechanisms underlying their cisplatin resistance are distinct. In OV433 cells, cisplatin resistance is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). By knocking down MKP-1 expression by siRNA or inhibiting MKP-1 expression by its pharmacological inhibitor triptolide, cisplatin-resistant OV433 cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. In tOV112D cells, on the other hand, acquired cisplatin resistance is associated with increased levels of Bcl-2 protein. By inhibiting the activity of Bcl-2 protein with its pharmacological inhibitor gossypol or knocking down Bcl-2 expression by siRNA, cisplatin-resistant tOV112D cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. therefore, our data suggest that the mechanisms of acquired cisplatin resistance vary among ovarian cancer cells, which involve upregulation of molecules associated with the cell survival pathways.
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