title: Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.
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.
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Cheng
authors.identifier: http://orcid.org/0000-0003-3864-8382
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Changliang
authors.identifier: http://orcid.org/0000-0002-4906-1686
authors.initials: C
authors.lastname: Shan
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Qiancheng
authors.initials: Q
authors.lastname: You
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Laboratory of Chemical Biology, Eindhoven University of Technology, 5600 MB Eindhoven, Netherlands.
authors.forename: Jan L
authors.initials: JL
authors.lastname: Vinkenborg
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Heebum
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Dali
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Karpus
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shisheng
authors.initials: S
authors.lastname: Ouyang
authors.affiliation: Department of Molecular BioSciences, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Chihao
authors.initials: C
authors.lastname: Luan
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.affiliation: Laboratory of Chemical Biology, Eindhoven University of Technology, 5600 MB Eindhoven, Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Merkx
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecule Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.|Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D055808:Drug Discovery; D055785:Gene Knockdown Techniques; D006801:Humans; D056511:Metallochaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016415:Sequence Alignment; D023041:Xenograft Model Antitumor Assays
chemical_list: C474500:ATOX1 protein, human; D000970:Antineoplastic Agents; C114678:CCS protein, human; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D003300:Copper