Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death
Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death
复制标题
阻断 SLC31A1 依赖性铜吸收可增加胰腺癌细胞自噬以抵抗细胞死亡
DOI：
10.1111/cpr.12568
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发表时间：
2019-03-01
影响因子：
8.5
通讯作者：
Teng, Chun-Bo
中科院分区：
文献类型：
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作者：
Yu, Ze;Zhou, Rongtao;Teng, Chun-Bo
临床观察表明，铜水平升高，在几种癌症类型，和铜剥夺显示抑制肿瘤血管生成和生长在动物模型和临床前试验。然而，铜在胰腺导管腺癌（PDAC）中的含量以及它是否是一个潜在的治疗靶点仍然是未知的。材料与方法采用电感耦合等离子体质谱法（ICP-MS）测定PDAC中铜的含量。通过铜转运蛋白1（SLC 31 A1）干扰和铜螯合剂四硫代钼酸盐（TM）处理进行Panc-1或MiaPaCa-2细胞中的铜消耗。从细胞增殖、迁移、侵袭、集落形成和细胞凋亡等方面评价铜剥夺对肿瘤细胞的影响。通过线粒体功能障碍测试和自噬研究解决了铜剥夺引起的癌细胞静止的机制。在铜阻断和/或自噬抑制条件下进行体外和异种移植小鼠的肿瘤抑制实验。结果SLC 31 A1依赖性铜水平与胰腺癌恶性程度相关。阻断铜的吸收可以抑制胰腺癌的进展，但不会增加细胞死亡。我们发现，铜剥夺增加线粒体ROS水平，降低ATP水平，使癌细胞处于休眠状态。引人注目的是，铜剥夺导致自噬增加以抵抗胰腺癌细胞的死亡。同时用TM和自噬抑制剂CQ治疗增加了体外癌细胞的细胞死亡，并延缓了体内癌细胞的生长。结论这些发现表明，铜缺乏引起的细胞休眠和自噬的增加是铜缺乏疗法治疗癌症的临床结果不佳的原因。因此，自噬抑制和铜耗竭的组合可能是治疗胰腺癌和其他铜依赖性恶性肿瘤的新策略。
Objectives Clinical observations have demonstrated that copper levels elevate in several cancer types, and copper deprivation is shown to inhibit tumour angiogenesis and growth in both animal models and preclinical trials. However, the content of copper in pancreatic duct adenocarcinoma (PDAC) and whether it is a potential therapy target is still unknown. Materials and Methods The levels of copper in PDAC specimens were detected by ICP-MS assays. Copper depletion in Panc-1 or MiaPaCa-2 cells was conducted via copper transporter 1 (SLC31A1) interference and copper chelator tetrathiomolybdate (TM) treatment. The effects of copper deprivation on cancer cells were evaluated by cell proliferation, migration, invasion, colony formation and cell apoptosis. The mechanism of copper deprivation-caused cancer cell quiescence was resolved through mitochondrial dysfunction tests and autophagy studies. The tumour-suppression experiments under the condition of copper block and/or autophagy inhibition were performed both in vitro and in xenografted mice. Results SLC31A1-dependent copper levels are correlated with the malignant degree of pancreatic cancer. Blocking copper absorption could inhibit pancreatic cancer progression but did not increase cell death. We found that copper deprivation increased mitochondrial ROS level and decreased ATP level, which rendered cancer cells in a dormant state. Strikingly, copper deprivation caused an increase in autophagy to resist death of pancreatic cancer cells. Simultaneous treatment with TM and autophagy inhibitor CQ increased cell death of cancer cells in vitro and retarded cancer growth in vivo. Conclusions These findings reveal that copper deprivation-caused cell dormancy and the increase in autophagy is a reason for the poor clinical outcome obtained from copper depletion therapies for cancers. Therefore, the combination of autophagy inhibition and copper depletion is potentially a novel strategy for the treatment of pancreatic cancer and other copper-dependent malignant tumours.