Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy
Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy
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DOI：
10.1007/s00775-013-1087-0
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发表时间：
2014-03-01
影响因子：
3
通讯作者：
Anderson, Carolyn J.
中科院分区：
文献类型：
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作者：
Beaino, Wissam;Guo, Yunjun;Anderson, Carolyn J.
由于其细胞毒性，游离铜被蛋白质侧链螯合，并且在体内不存在。一些伴侣将铜转运至不同的细胞区室，但尚未发现将铜转运至细胞核的伴侣。 Copper-64 通过 β(+) 和 β(-) 发射进行衰变，从而允许正电子发射断层扫描和癌症的靶向放射性核素治疗。由于将 Cu-64 递送至细胞核可能会增强铜放射性药物的治疗效果，因此阐明将铜转运至肿瘤细胞核所涉及的途径对于优化治疗非常重要。我们确定 Atox1 是细胞核中结合铜的蛋白质之一。 Atox1 阳性和阴性的小鼠胚胎成纤维细胞用于确定 Atox1 在 Cu-64 转运至细胞核中的作用。小鼠胚胎成纤维细胞Atox1(+/+)在细胞核中比Atox1(-/-)细胞积累更多的Cu-64。使用表达 p53 (+/+) 和不表达 p53 (-/-) 的 HCT 116 结直肠癌细胞来评估该肿瘤抑制蛋白在 Cu-64 转运中的作用。在顺铂处理的细胞中，HCT 116 p53(+/+)细胞核对Cu-64的摄取高于HCT 116 p53(-/-)细胞。顺铂处理的HCT 116 p53(+/+)和p53(-/-)细胞中Atox1表达增加；然而，Atox1 更定位于 p53(+/+) 细胞的细胞核，而不是 p53(-/-) 细胞。这里提供的数据表明 Atox1 参与铜向细胞核的转运，顺铂通过上调 Atox1 的表达和核定位来影响 HCT 116 细胞中 Cu-64 的核转运。
Owing to its cytotoxicity, free copper is chelated by protein side chains and does not exist in vivo. Several chaperones transport copper to various cell compartments, but none have been identified that traffic copper to the nucleus. Copper-64 decays by beta(+) and beta(-) emission, allowing positron emission tomography and targeted radionuclide therapy for cancer. Because the delivery of Cu-64 to the cell nucleus may enhance the therapeutic effect of copper radiopharmaceuticals, elucidation of the pathway(s) involved in transporting copper to the tumor cell nucleus is important for optimizing treatment. We identified Atox1 as one of the proteins that binds copper in the nucleus. Mouse embryonic fibroblast cells, positive and negative for Atox1, were used to determine the role of Atox1 in Cu-64 transport to the nucleus. Mouse embryonic fibroblast Atox1(+/+) cells accumulated more Cu-64 in the nucleus than did Atox1(-/-) cells. HCT 116 colorectal cancer cells expressing p53 (+/+) and not expressing p53 (-/-) were used to evaluate the role of this tumor suppressor protein in Cu-64 transport. In cells treated with cisplatin, the uptake of Cu-64 in the nucleus of HCT 116 p53(+/+) cells was greater than that in HCT 116 p53(-/-) cells. Atox1 expression increased in HCT 116 p53(+/+) and p53(-/-) cells treated with cisplatin; however, Atox1 localized to the nuclei of p53(+/+) cells more than in the p53(-/-) cells. The data presented here indicate that Atox1 is involved in copper transport to the nucleus, and cisplatin affects nuclear transport of Cu-64 in HCT 116 cells by upregulating the expression and the nuclear localization of Atox1.