Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A
Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A
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DOI：
10.1002/ijc.28526
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发表时间：
2014-04-15
影响因子：
6.4
通讯作者：
Naka, Tetsuji
中科院分区：
文献类型：
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作者：
Matsuzaki, Shinya;Enomoto, Takayuki;Naka, Tetsuji
虽然铂类药物常用于人类癌症的化疗，但铂类药物耐药性是一个主要问题，在某些情况下可能会妨碍其使用。我们最近报道了膜联蛋白A4（Anx A4）表达增强通过增加药物的细胞外流出增加对卡铂的耐药性。然而，化疗耐药性的确切机制以及体内Anx A4与铂耐药性的关系仍不清楚。在这份报告中，在体外的铂耐药诱导的Anx A4在子宫内膜癌细胞（HEC 1细胞）与低表达的Anx A4的机制进行了研究。Anx A4在HEC 1细胞中的强制表达导致对铂类药物的化疗耐药性。此外，在异种移植小鼠中将HEC 1对照细胞与Anx A4过表达的HEC 1细胞进行比较。在Anx A4过表达的异种移植小鼠中，体内观察到对顺铂的化疗耐药性显著增加。免疫荧光分析显示，暴露于铂类药物诱导Anx A4从细胞质迁移到细胞膜，在那里它与ATP 7A共定位，ATP 7A是一种铜转运蛋白，也是众所周知的铂外排机制。ATP 7A表达抑制小干扰RNA对HEC 1对照细胞的铂类药物的化疗敏感性没有影响。然而，在Anx A4过表达的铂类耐药细胞中抑制ATP 7A可将铂类药物（但不包括5-氟尿嘧啶）的化疗敏感性提高到与对照细胞相当的水平。这些结果表明，Anx A4的表达增强通过促进铂类药物经由ATP 7A的外排而赋予铂类耐药性。
Although platinum drugs are often used for the chemotherapy of human cancers, platinum resistance is a major issue and may preclude their use in some cases. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to carboplatin through increased extracellular efflux of the drug. However, the precise mechanisms underlying that chemoresistance and the relationship of Anx A4 to platinum resistance in vivo remain unclear. In this report, the in vitro mechanism of platinum resistance induced by Anx A4 was investigated in endometrial carcinoma cells (HEC1 cells) with low expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, HEC1 control cells were compared with Anx A4-overexpressing HEC1 cells in xenografted mice. Significantly greater chemoresistance to cisplatin was observed in vivo in Anx A4-overexpressing xenografted mice. Immunofluorescence analysis revealed that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became colocalized with ATP7A, a copper transporter also well known as a mechanism of platinum efflux. ATP7A expression suppressed by small interfering RNA had no effect on HEC1 control cells in terms of chemosensitivity to platinum drugs. However, suppression of ATP7A in Anx A4-overexpressing platinum-resistant cells improved chemosensitivity to platinum drugs (but not to 5-fluorouracil) to a level comparable to that of control cells. These results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A.