Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line
Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line
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DOI：
10.1021/bi047948g
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发表时间：
2005-02-22
期刊：
影响因子：
2.9
通讯作者：
Corey, DR
中科院分区：
文献类型：
--
作者：
Huffman, KE;Corey, DR
人主要穹窿蛋白（MVP）是13 MDa穹窿复合物的主要组分。MVP与癌细胞中非P-糖蛋白介导的耐药性的发展有关。在这里，我们提出了几条证据来反驳这一说法。能够特异性和有效地敲低MVP表达的siRNA不会改变耐药细胞从细胞核中去除阿霉素的能力，也不会增加对药物的敏感性。相反，MVP在化学敏感细胞中的上调并不赋予增加的耐药性。在多药耐药（MDR）肺癌细胞，荧光显微镜显示，阿霉素进入细胞核，然后被删除，不一致的建议，拱顶要么采取行动，以防止药物进入细胞核或参与作为核外排泵。这些数据表明，穹窿在非小细胞肺癌细胞的MDR表型中没有直接作用，并且它们的细胞功能仍然未知。这些结果对于MVP作为药物靶点和化疗失败的预后标志物的价值也有重要意义。我们的研究结果表明，需要进一步研究穹窿上调和恶性肿瘤之间的联系，背后的机制非P-gp介导的耐药性，以及穹窿在人类细胞中的作用。
The human major vault protein (MVP) is the primary component of the 13 MDa vault complex. MVP has been implicated in the development of non-P-glycoprotein-mediated drug resistance in cancer cells. Here we present several lines of evidence that dispute this assertion. siRNAs capable of specifically and efficiently knocking down expression of MVP do not alter the ability of resistant cells to remove doxorubicin from the nucleus and do not increase sensitivity to the drug. Conversely, upregulation of MVP in chemosensitive cells does not confer increased drug resistance. In multi-drug resistant (MDR) lung carcinoma cells, fluorescence microscopy reveals that doxorubicin enters the nucleus and is then removed, inconsistent with suggestions that vaults either act to prevent the drug from entering the nucleus or are involved as a nuclear efflux pump. These data suggest that vaults play no direct role in the MDR phenotype in non-small cell lung carcinoma cells and that their cellular function remains unknown. These results also have important implications concerning the value of MVP as a drug target and as a prognostic marker for chemotherapy failure. Our results suggest the need for further investigation into the link between upregulation of vaults and malignancy, the mechanism behind non-P-gp-mediated drug resistance, and the role of vaults in human cells.