Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

• Type of Material: Article
• Authors: Jing Wang, University of Chicago; Cheng Luo, Shanghai Institute of Materia Medica; Changliang Shan, Emory University; Qiancheng You, University of Chicago; Junyan Lu, Shanghai Institute of Materia Medica; Shannon Elf, Emory University; Yu Zhou, Shanghai Institute of Materia Medica; Yi Wen, Shanghai Institute of Materia Medica; Jan L. Vinkenborg, Eindhoven University of Technology; Jun Fan, Emory University; Heebum Kang, Emory University; Ruiting Lin, Emory University; Dali Han, University of Chicago; Yuxin Xie, University of Chicago; Jason Karpus, University of Chicago; Shijie Chen, Shanghai Institute of Materia Medica; Shisheng Ouyang, Shanghai Institute of Materia Medica; Chihao Luan, Northwestern University; Naixia Zhang, Shanghai Institute of Materia Medica; Hong Ding, Shanghai Institute of Materia Medica; Maarten Merkx, Eindhoven University of Technology; Hong Liu, Shanghai Institute of Materia Medica; Jing Chen, Emory University; Hualiang Jiang, Shanghai Institute of Materia Medica; Chuan He, University of Chicago
• Language: English
• Date: 2015-12-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Macmillan Publishers Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/NCHEM.2381
• Title of Journal or Parent Work: Nature Chemistry
• ISSN: 1755-4330
• Volume: 7
• Issue: 12
• Start Page: 968
• End Page: 979
• Grant/Funding Information: This work was supported by grants from the National Natural Science Foundation of China (21210003 to H.J. and C.H., and 81230076, 91313000 to H.J.), the Hi-Tech Research and Development Program of China (2012AA020302 and 2012AA01A305 to C.L.), Chinese Academy of Sciences (XDA01040305 to C.L.), National Science Foundation (CHE-1213598 to C.H.) and National Institutes of Health (CA140515 to J.C.).; C.H. is supported by the Howard Hughes Medical Institute as an investigator.
• Keywords: MECHANISMS; DISEASE; Physical Sciences; HOMEOSTASIS; CHAPERONE; ANTICANCER STRATEGY; Chemistry; METABOLISM; OXIDATIVE STRESS; METALLOCHAPERONE; Chemistry, Multidisciplinary; SUPEROXIDE-DISMUTASE; TARGET; Science & Technology

Abstract

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.