Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.
Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.
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DOI：
10.1007/s00775-013-1051-z
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发表时间：
2014-01
影响因子：
3
通讯作者：
Kuo, Macus Tien
中科院分区：
文献类型：
--
作者：
Liang, Zheng Dong;Long, Yan;Chen, Helen H. W.;Savaraj, Niramol;Kuo, Macus Tien
铂类抗肿瘤药物已成为人类多种恶性肿瘤化疗的主要药物。耐药性是实现这些药物的最大治疗功效的重要障碍。了解铂类药物如何进入细胞对于提高治疗效果非常重要。已经证明，人高亲和力铜转运蛋白1（hCtr 1）参与将顺铂转运到细胞中以引起细胞毒性作用，尽管可能存在其他机制。在这篇文章中，我们证明顺铂以时间和浓度依赖的方式转录诱导hCtr 1的表达。顺铂作为hCtr 1介导的铜转运的竞争者发挥作用，导致细胞铜水平降低并导致Sp1表达上调，Sp1是hCtr 1表达的正调节因子。因此，顺铂对hCtr 1表达的调节是铜稳态调节系统的组成部分。我们还表明，银（I）和锌（II），这是已知的抑制hCtr 1介导的铜转运，也可以诱导hCtr 1/Sp1的表达。相反，镉（II），铜转运的另一种抑制剂，下调hCtr 1的表达抑制Sp1的表达。总的来说，我们的研究结果表明，这些重金属调节铜代谢的不同机制。
Platinum-based antitumor agents have been the mainstay in cancer chemotherapy for many human malignancies. Drug resistance is an important obstacle to achieving the maximal therapeutic efficacy of these drugs. Understanding how platinum drugs enter cells is of great importance in improving therapeutic efficacy. It has been demonstrated that human high-affinity copper transporter 1 (hCtr1) is involved in transporting cisplatin into cells to elicit cytotoxic effects, although other mechanisms may exist. In this communication, we demonstrate that cisplatin transcriptionally induces the expression of hCtr1 in time- and concentration-dependent manners. Cisplatin functions as a competitor for hCtr1-mediated copper transport, resulting in reduced cellular copper levels and leading to upregulated expression of Sp1, which is a positive regulator for hCtr1 expression. Thus, regulation of hCtr1 expression by cisplatin is an integral part of the copper homeostasis regulation system. We also demonstrate that Ag(I) and Zn(II), which are known to suppress hCtr1-mediated copper transport, can also induce hCtr1/Sp1 expression. In contrast, Cd(II), another inhibitor of copper transport, downregulates hCtr1 expression by suppressing Sp1 expression. Collectively, our results demonstrate diverse mechanisms of regulating copper metabolism by these heavy metals.
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影响因子：
10.6
作者：
Jeong, Jeeyon;Eide, David J.
通讯作者：
Eide, David J.
影响因子：
3.6
作者：
Chen, Helen H. W.;Song, Im-Sook;Kuo, Macus Tien
通讯作者：
Kuo, Macus Tien
影响因子：
5.3
作者：
Chen, Helen H. W.;Yan, Jiang-Jou;Chen, Wen-Chung;Kuo, Macus Tien;Lai, Yu-Hsuan;Lai, Wu-Wei;Liu, Hsiao-Sheng;Su, Wu-Chou
通讯作者：
Su, Wu-Chou
影响因子：
5.8
作者：
Hour TC;Lai YL;Kuan CI;Chou CK;Wang JM;Tu HY;Hu HT;Lin CS;Wu WJ;Pu YS;Sterneck E;Huang AM
通讯作者：
Huang AM
影响因子：
3.6
作者：
Liang, Zheng D.;Tsai, Wen-Bin;Kuo, Macus Tien
通讯作者：
Kuo, Macus Tien