Journal
ADVANCED SCIENCE
Volume 8, Issue 18, Pages -Publisher
WILEY
DOI: 10.1002/advs.202004303
Keywords
AKT; breast cancer; copper; CTR1; Nedd4l; PDK1
Categories
Funding
- NIH [CA177910]
- National Natural Science Foundation of China [32070767, 31871410, 81902487]
- China Postdoctoral Science Foundation [2020M672954]
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Copper activates the PI3K-AKT oncogenic signaling pathway to promote tumorigenesis, while CTR1 is abnormally elevated in breast cancer and regulated by Nedd4l-mediated ubiquitination. Targeting the CTR1-copper node may have therapeutic relevance for hyperactive AKT-driven cancers.
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.
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