title: A re-evaluation of the role of hCTR1, the human high-affinity copper transporter, in platinum-drug entry into human cells.
abstract: Cisplatin (cDDP) is an anticancer drug used in a number of malignancies, including testicular, ovarian, cervical, bladder, lung, head, and neck cancers. Its use is limited by the development of resistance, often rationalized via effects on cellular uptake. It has been claimed that human copper transporter 1 (hCTR1), the human high-affinity copper transporter, is the major entry pathway for cDDP and related drugs via a mechanism that mimics copper. This is an unexpected property of hCTR1, a highly selective copper (I) transporter. We compared the uptake rates of copper with cDDP (and several analogs) into human embryonic kidney 293 cells overexpressing wild-type or mutant hCTR1, mouse embryonic fibroblasts that do or do not express CTR1, and human ovarian tumor cells that are sensitive or resistant to cDDP. We have also compared the effects of extracellular copper, which causes regulatory endocytosis of hCTR1, to those of cDDP. We confirm the correlation between higher hCTR1 levels and higher platinum drug uptake in tumor cells sensitive to the drug. However, we show that hCTR1 is not the major entry route of platinum drugs, and that the copper transporter is not internalized in response to extracellular drug. Our data suggest the major entry pathway for platinum drugs is not saturable at relevant concentrations and not protein-mediated. Clinical trials have been initiated that depend upon regulating membrane levels of hCTR1. If reduced drug uptake is a major factor in resistance, hCTR1 is unlikely to be a productive target in attempts to enhance efficacy, although the proteins involved in copper homeostasis may play a role.
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Ivy
authors.forename: Jack H
authors.initials: JH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; D002945:Cisplatin
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14298-302
references.pmid: 12370430
references.citation: Mol Pharmacol. 2004 Oct;66(4):817-23
references.pmid: 15229296
references.citation: Mol Cancer Ther. 2004 Dec;3(12):1543-9
references.pmid: 15634647
references.citation: Cancer Res. 2006 Nov 15;66(22):10944-52
references.pmid: 17108132
references.citation: Cancer Res. 2000 Mar 1;60(5):1312-6
references.pmid: 10728692
references.citation: Cancer Treat Rev. 2007 Feb;33(1):9-23
references.pmid: 17084534
references.citation: Clin Cancer Res. 2004 Oct 1;10(19):6744-9
references.pmid: 15475465
references.citation: Cancer Chemother Pharmacol. 2009 Jun;64(1):133-42
references.pmid: 18998134
references.citation: J Biol Chem. 2004 Nov 5;279(45):46393-9
references.pmid: 15326162
references.citation: Clin Cancer Res. 2009 Jan 15;15(2):553-60
references.pmid: 19147760
references.citation: Mol Pharmacol. 2002 Nov;62(5):1154-9
references.pmid: 12391279
references.citation: Cancer Cell. 2010 Jun 15;17(6):574-83
references.pmid: 20541702
references.citation: Clin Pharmacol Ther. 2009 Oct;86(4):396-402
references.pmid: 19625999
references.citation: Mol Pharmacol. 2009 Oct;76(4):843-53
references.pmid: 19570948
references.citation: Cancer Cells. 1990 Feb;2(2):35-43
references.pmid: 2204382
references.citation: Biochem Pharmacol. 2012 Oct 15;84(8):1007-13
references.pmid: 22842628
references.citation: J Biol Chem. 2009 Sep 18;284(38):25461-5
references.pmid: 19602511
references.citation: Cancer Res. 1988 Jan 1;48(1):68-73
references.pmid: 3335000
references.citation: Cancer Res. 2002 Nov 15;62(22):6559-65
references.pmid: 12438251
references.citation: J Biol Chem. 2003 Mar 14;278(11):9639-46
references.pmid: 12501239
references.citation: J Biol Chem. 2007 Jul 13;282(28):20376-87
references.pmid: 17525160
references.citation: J Biol Chem. 2002 Oct 25;277(43):40253-9
references.pmid: 12177073
references.citation: Mol Cancer Ther. 2012 Jun;11(6):1221-5
references.pmid: 22491798
references.citation: J Biol Chem. 2009 Oct 23;284(43):29704-13
references.pmid: 19740744
references.citation: Biometals. 2007 Jun;20(3-4):705-16
references.pmid: 17211682
references.citation: Mol Pharmacol. 2009 Feb;75(2):324-30
references.pmid: 18996970
references.citation: Ann Intern Med. 1984 May;100(5):704-13
references.pmid: 6370067
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6951-6
references.pmid: 21482801
references.citation: Cancer Chemother Pharmacol. 2009 Mar;63(4):643-50
references.pmid: 18545997
references.citation: Drug Metab Pharmacokinet. 2007 Feb 25;22(1):33-40
references.pmid: 17329909
references.citation: J Am Chem Soc. 2004 Mar 31;126(12):3928-38
references.pmid: 15038747
references.citation: Circ Res. 2010 Sep 17;107(6):787-99
references.pmid: 20671235
references.citation: Br J Cancer. 1993 Jun;67(6):1171-6
references.pmid: 8512802
references.citation: Cell. 1994 Jan 28;76(2):393-402
references.pmid: 8293472
references.citation: Mol Pharmacol. 2004 Jul;66(1):25-32
references.pmid: 15213293
references.citation: Nat Rev Cancer. 2007 Aug;7(8):573-84
references.pmid: 17625587
references.citation: Am J Physiol Cell Physiol. 2011 Mar;300(3):C588-99
references.pmid: 21191107
references.citation: Pflugers Arch. 2004 Feb;447(5):666-76
references.pmid: 12883891
references.citation: Rev Gastroenterol Peru. 2001 Oct-Dec;21(4):276-81
references.pmid: 11818988
references.citation: Biochem Pharmacol. 2010 Aug 15;80(4):448-54
references.pmid: 20451502
references.citation: Lung Cancer. 2012 Feb;75(2):228-34
references.pmid: 21788094
references.citation: Biochem Pharmacol. 2007 Jan 15;73(2):298-307
references.pmid: 17097621
references.citation: Am J Physiol Renal Physiol. 2009 Mar;296(3):F505-11
references.pmid: 19144690
references.citation: Drugs. 2000;59 Suppl 4:9-17; discussion 37-8
references.pmid: 10864226
references.citation: Cancer Res. 1973 Apr;33(4):813-8
references.pmid: 4735238
references.citation: J Inorg Biochem. 2012 Nov;116:1-10
references.pmid: 23010323
references.citation: J Biol Chem. 2007 Sep 7;282(36):26471-80
references.pmid: 17627945
references.citation: J Biol Chem. 2002 Aug 9;277(32):29162-71
references.pmid: 12034741
references.citation: Mol Pharmacol. 2010 Sep;78(3):333-9
references.pmid: 20519567
references.citation: Biochem Pharmacol. 2004 Jul 15;68(2):283-91
references.pmid: 15194000
references.citation: J Biol Chem. 2007 Sep 14;282(37):26775-26785
references.pmid: 17627943