Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin.
Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin.
复制标题
DOI：
10.18632/oncotarget.12992
复制
发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Deng CX
中科院分区：
文献类型：
--
作者：
Chisholm CL;Wang H;Wong AH;Vazquez-Ortiz G;Chen W;Xu X;Deng CX
顺铂是一种有效的乳腺癌药物，但长期化疗往往会产生耐药性。因此，我们结合顺铂治疗进行了候选方法的RNAi筛选，以确定赋予生存优势的分子途径。屏幕将ATP7A确定为治疗靶点。ATP7A是一种铜ATPase转运体，负责顺铂的细胞间运动和隔离。用四硫代钼酸铵(TM)药物替代ATP7A增强顺铂对乳腺癌细胞的治疗。与单纯顺铂或TM治疗相比，顺铂/TM治疗裸鼠同种异体移植瘤模型显示肿瘤生长缓慢，肿瘤干细胞积聚减少，细胞增殖减少。顺铂/TM治疗顺铂耐药肿瘤降低了ATP7A蛋白水平，减弱了ATP7A对顺铂的滞留，增加了顺铂的核可利用性，从而增强了DNA损伤和细胞凋亡。对对顺铂/TM双重处理有独特反应的基因本体论途径的微阵列分析描述了细胞周期调节的变化，特别是在G1/S的转变中。这些发现提供了对抗铂耐药肿瘤的潜力，并通过识别和靶向耐药肿瘤的独特分子适应来提高患者对传统乳腺癌治疗的敏感性。
Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations.