Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner.
Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner.
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铜通过以铜转运蛋白 1 依赖性方式激活 PDK-AKT 致癌途径来促进肿瘤发生
DOI：
10.1002/advs.202004303
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Guo J;Cheng J;Zheng N;Zhang X;Dai X;Zhang L;Hu C;Wu X;Jiang Q;Wu D;Okada H;Pandolfi PP;Wei W
铜在代谢平衡中起着关键作用，但其在人类肿瘤发生中的潜在作用尚不清楚。本研究发现，铜激活磷酸肌苷3激酶(PI3K) -蛋白激酶B （PKB，也称为AKT）致癌信号通路，促进肿瘤发生。从机制上讲，铜结合3‐磷酸肌苷依赖性蛋白激酶1 (PDK1)，进而促进PDK1结合，随后激活其下游底物AKT，促进肿瘤发生。通过消耗CTR1或使用铜螯合剂阻断铜转运蛋白1 (CTR1) -铜轴可减少AKT信号传导并减少肿瘤发生。为了支持CTR1的致癌作用，作者发现CTR1在乳腺癌中异常升高，并且通过泛素化和随后的降解受到NEDD4样E3泛素蛋白连接酶（Nedd4l）介导的负调控。因此，Nedd4l通过抑制CTR1‐AKT信号通路显示出肿瘤抑制功能。因此，研究结果确定了Nedd4l‐CTR1‐铜轴和PDK1‐AKT致癌信号之间的一种新的调控串扰，并强调了靶向CTR1‐铜节点治疗过度活跃的AKT‐驱动的癌症的治疗相关性。除了在代谢平衡中发挥关键作用外，铜还可以结合PDK1激活其下游AKT激酶，从而促进肿瘤的发生。同时，铜转运蛋白1 （CTR1）受到Nedd4l介导的泛素化和随后的降解的负调控，表明Nedd4l - CTR1 -铜轴与PDK1 - AKT致癌信号之间存在新的调控串扰，从而调控肿瘤的发生。
Copper plays pivotal roles in metabolic homoeostasis, but its potential role in human tumorigenesis is not well defined. Here, it is revealed that copper activates the phosphoinositide 3‐kinase (PI3K)‐protein kinase B (PKB, also termed AKT) oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper binds 3‐phosphoinositide dependent protein kinase 1 (PDK1), in turn promotes PDK1 binding and subsequently activates its downstream substrate AKT to facilitate tumorigenesis. Blocking the copper transporter 1 (CTR1)‐copper axis by either depleting CTR1 or through the use of copper chelators diminishes the AKT signaling and reduces tumorigenesis. In support of an oncogenic role for CTR1, the authors find that CTR1 is abnormally elevated in breast cancer, and is subjected by NEDD4 like E3 ubiquitin protein ligase (Nedd4l)‐mediated negative regulation through ubiquitination and subsequent degradation. Accordingly, Nedd4l displays a tumor suppressive function by suppressing the CTR1‐AKT signaling. Thus, the findings identify a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling, and highlight the therapeutic relevance of targeting the CTR1‐copper node for the treatment of hyperactive AKT‐driven cancers. Besides playing pivotal roles in metabolic homoeostasis, copper also binds PDK1 to activate its downstream AKT kinase, which in turn facilitates tumorigenesis. Meanwhile, the copper transporter 1 (CTR1) is negatively regulated by Nedd4l‐mediated ubiquitination and subsequent degradation, indicating a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling to govern tumorigenesis.
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