Impaired activity of volume-sensitive Cl- channel is involved in cisplatin resistance of cancer cells
Impaired activity of volume-sensitive Cl- channel is involved in cisplatin resistance of cancer cells
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DOI：
10.1002/jcp.20961
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Okada, Yasunobu
中科院分区：
文献类型：
--
作者：
Lee, Elbert L.;Shimizu, Takahiro;Okada, Yasunobu
基于铂的药物顺铂是一种广泛使用的抗癌药物，其通过引起细胞凋亡的诱导起作用。然而，对药物的耐药性是一个主要问题。在这项研究中，我们表明，KCP-4人表皮样癌细胞系，作为一个模型的获得性耐顺铂，几乎没有体积敏感，向外整流（VSOR）氯离子通道的活动。VSOR氯离子通道的分子身份尚未确定，本研究中的半定量RT-PCR实验表明，该通道与三个候选基因中的任何一个都不对应。然而，因为它是已知的，通道电流在细胞凋亡中起着至关重要的作用，我们假设，缺乏电流有助于顺铂耐药在这些细胞中，它的恢复将降低电阻。为了验证这一假设，我们试图恢复KCP-4细胞中的VSOR氯电流。研究发现，用组蛋白脱乙酰酶抑制剂-用TSA和顺铂处理细胞导致在24 h时半胱天冬酶-3活性增加和在48 h时细胞活力降低。这些作用被阻断的同时处理的细胞与VSOR氯离子通道阻滞剂。这些结果表明，通过TSA处理恢复通道的功能表达导致KCP-4细胞的顺铂抗性降低。因此，我们得出结论，受损的VSOR氯离子通道的活性参与顺铂耐药的KCP-4癌细胞。
The platinum-based drug cisplatin is a widely used anticancer drug which acts by causing the induction of apoptosis. However, resistance to the drug is a major problem. In this study we show that the KCP-4 human epidermoid cancer cell line, which serves as a model of acquired resistance to cisplatin, has virtually no volume-sensitive, outwardly rectifying (VSOR) chloride channel activity. The VSOR chloride channel's molecular identity has not yet been determined, and semi-quantitative RT-PCR experiments in this study suggested that the channel corresponds to none of three candidate genes. However, because it is known that the channel current plays an essential role in apoptosis, we hypothesized that lack of the current contributes to cisplatin resistance in these cells and that its restoration would reduce resistance. To test this hypothesis, we attempted to restore VSOR chloride current in KCP-4 cells. It was found that treatment with trichostatin A (TSA), a histone deacetylase inhibitor, caused VSOR chloride channel function to be partially restored. Treatment of the cells with both TSA and cisplatin resulted in an increase in caspase-3 activity at 24 h and a decrease in cell viability at 48 h. These effects were blocked by simultaneous treatment of the cells with a VSOR chloride channel blocker. These results indicate that restoration of the channel's functional expression by TSA treatment leads to a decrease in the cisplatin resistance of KCP-4 cells. We thus conclude that impaired activity of the VSOR chloride channel is involved in the cisplatin resistance of KCP-4 cancer cells.