Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line
Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line
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细胞角蛋白8和乳腺癌耐药蛋白的共表达表明人乳腺癌细胞系中存在多因素耐药表型
DOI：
10.1016/j.lfs.2008.07.017
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发表时间：
2008-09-26
期刊：
影响因子：
6.1
通讯作者：
Xiong, Dongsheng
中科院分区：
文献类型：
--
作者：
Liu, Fang;Fan, Dongmei;Xiong, Dongsheng
目的：目的是确定 CK8 和 BCRP 表达增加是否共同导致 MCF-7/MX 细胞的多药耐药性 (MDR)。越来越多的证据表明，癌症 MDR 的发展和维持涉及复杂的多模式机制，这些机制同时相互作用且互补。在本报告中，我们观察到MCF-7/MX（一种米托蒽醌（MX）选择的具有多药耐药表型的人乳腺癌细胞系MCF-7/MX）中细胞角蛋白8（CK8）的表达升高，称为乳腺癌耐药蛋白（BCRP）的过度表达。主要方法：采用基因转染方法在NIH3T3成纤维细胞中单独或联合表达CK8和BCRP。 主要发现：总而言之，我们目前的研究表明，CK8 与 BCRP 一起可能在赋予 MCF-7/MX 细胞的多因素 MDR 表型中发挥重要作用，但可能通过潜在不同的机制独立发挥作用。虽然单独表达 CK8 或 BCRP 能够赋予米托蒽醌耐药性，但共表达两种蛋白的细胞表现出显着增加的耐药性。此外，在MCF-7/MX细胞中单独或联合RNAi敲低CK8和BCRP可显着减弱它们对化疗药物的耐药性。有趣的是，与通过抗 BCRP shRNA 载体转染抑制 BCRP 表达相反，通过抗 CK8 shRNA 转染逆转米托蒽醌耐药性并不伴随细胞内药物积累的增加。意义：针对癌细胞中多种耐药相关分子/途径的组合方法可能代表更有效的克服 MDR 的策略。 (C) 2008 Elsevier Inc. 保留所有权利。
Aims: The aim was to determine whether increased CK8 and BCRP expression cooperatively contribute to multidrug resistance (MDR) in MCF-7/MX cells.Accumulating evidence suggests that the development and maintenance of cancer MDR involves complex multimodal mechanisms that interact concomitantly and complementarily. In this report, we observed elevated expression of cytokeratin 8 (CK8) in MCF-7/MX) a mitoxantrone (MX)-selected human breast tumor cell line with the MDR phenotype known as overexpression of breast cancer resistant protein (BCRP).Main methods: Gene transfection methods were used to express CK8 and BCRP in NIH3T3 fibroblasts, individually or in combination.Key findings: Taken together, our present study suggests that CK8 together with BCRP may play significant roles in conferring the multifactorial MDR phenotype of MCF-7/MX cells, but may act independently via potentially different mechanisms.Although expressing either CK8 or BCRP alone was able to confer resistance to mitoxantrone, cells co-expressing both proteins demonstrated significantly increased drug resistance. Furthermore, RNAi knockdown of CK8 and BCRP, alone and in combination, in MCF-7/MX cells significantly attenuated their resistance to chemotherapeutic agents. Interestingly, in contrast to inhibition of BCRP expression via anti-BCRP shRNA vector transfection, reversal of mitoxantrone resistance by transfection with anti-CK8 shRNA was not accompanied by an increase in intracellular drug accumulation.Significance: Combinational approaches that target multiple drug-resistance-related molecules/pathways in cancer cells may represent more efficacious strategies to overcome MDR. (C) 2008 Elsevier Inc. All rights reserved.