Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-18 , DOI: 10.1002/advs.202004303
Jianping Guo _{1,

2} , Ji Cheng _{1,

3} , Nana Zheng ₄ , Xiaomei Zhang ₂ , Xiaoming Dai ₁ , Linli Zhang ₅ , Changjiang Hu ₁ , Xueji Wu ₂ , Qiwei Jiang ₂ , Depei Wu ₄ , Hitoshi Okada ₆ , Pier Paolo Pandolfi ₇ , Wenyi Wei ₁

Affiliation

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.

中文翻译：

铜以铜转运蛋白 1 依赖性方式激活 PDK1-AKT 致癌途径，促进肿瘤发生

铜在代谢稳态中发挥着关键作用，但其在人类肿瘤发生中的潜在作用尚不清楚。研究表明，铜可激活磷酸肌醇 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-磷酸肌醇依赖性蛋白激酶 1 (PDK1)，进而促进 PDK1 结合，随后激活其下游底物 AKT 以促进肿瘤发生。通过消耗CTR1或使用铜螯合剂来阻断铜转运蛋白 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 等 E3 泛素蛋白连接酶 (Nedd4l) 介导的负调节。因此，Nedd4l 通过抑制 CTR1-AKT 信号传导来显示肿瘤抑制功能。因此，这些发现确定了 Nedd4l-CTR1-铜轴和 PDK1-AKT 致癌信号传导之间的新型调控串扰，并强调了靶向 CTR1-铜节点对于治疗过度活跃的 AKT 驱动的癌症的治疗相关性。

更新日期：2021-09-22

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11