title: Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.
abstract: Platinum-based antitumor agents have been the mainstay in cancer chemotherapy for many human malignancies. Drug resistance is an important obstacle to achieving the maximal therapeutic efficacy of these drugs. Understanding how platinum drugs enter cells is of great importance in improving therapeutic efficacy. It has been demonstrated that human high-affinity copper transporter 1 (hCtr1) is involved in transporting cisplatin into cells to elicit cytotoxic effects, although other mechanisms may exist. In this communication, we demonstrate that cisplatin transcriptionally induces the expression of hCtr1 in time- and concentration-dependent manners. Cisplatin functions as a competitor for hCtr1-mediated copper transport, resulting in reduced cellular copper levels and leading to upregulated expression of Sp1, which is a positive regulator for hCtr1 expression. Thus, regulation of hCtr1 expression by cisplatin is an integral part of the copper homeostasis regulation system. We also demonstrate that Ag(I) and Zn(II), which are known to suppress hCtr1-mediated copper transport, can also induce hCtr1/Sp1 expression. In contrast, Cd(II), another inhibitor of copper transport, downregulates hCtr1 expression by suppressing Sp1 expression. Collectively, our results demonstrate diverse mechanisms of regulating copper metabolism by these heavy metals.
authors.affiliation: Department of Translational Molecular Pathology (Route 2951), The University of Texas MD Anderson Cancer Center, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Zheng Dong
authors.initials: ZD
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.forename: Helen H W
authors.initials: HH
authors.lastname: Chen
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019216:Metals, Heavy / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D019216:Metals, Heavy; D003300:Copper; D002945:Cisplatin