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PMID: 12370430 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 22 ·2002-10-29 ·Pages 14298-302

Ishida S, Lee J, Thiele DJ, Herskowitz I

Abstract

Cisplatin is a chemotherapeutic drug used to treat a variety of cancers. Both intrinsic and acquired resistance to cisplatin, as well as toxicity, limit its effectiveness. Molecular mechanisms that underlie cisplatin resistance are poorly understood. Here we demonstrate that deletion of the yeast CTR1 gene, which encodes a high-affinity copper transporter, results in increased cisplatin resistance and reduced intracellular accumulation of cisplatin. Copper, which causes degradation and internalization of Ctr1 protein (Ctr1p), enhances survival of wild-type yeast cells exposed to cisplatin and reduces cellular accumulation of the drug. Cisplatin also causes degradation and delocalization of Ctr1p and interferes with copper uptake in wild-type yeast cells. Mouse cell lines lacking one or both mouse Ctr1 (mCtr1) alleles exhibit increased cisplatin resistance and decreased cisplatin accumulation in parallel with mCtr1 gene dosage. We propose that cisplatin uptake is mediated by the copper transporter Ctr1p in yeast and mammals. The link between Ctr1p and cisplatin transport may explain some cases of cisplatin resistance in humans and suggests ways of modulating sensitivity and toxicity to this important anticancer drug.

MeSH Terms
Animals Antineoplastic Agents/metabolism,pharmacology Biological Transport Cation Transport Proteins Cell Line Cisplatin/metabolism,pharmacology Copper Radioisotopes/pharmacokinetics Copper Transporter 1 Drug Resistance, Fungal/genetics Drug Resistance, Neoplasm Mammals Membrane Proteins/genetics,metabolism,physiology Mice Saccharomyces cerevisiae/drug effects,metabolism Saccharomyces cerevisiae Proteins
Chemicals
Antineoplastic Agents CTR1 protein, S cerevisiae Cation Transport Proteins Copper Radioisotopes Copper Transporter 1 Membrane Proteins Saccharomyces cerevisiae Proteins Slc31a1 protein, mouse Cisplatin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ishida Seiko
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448, USA.
Lee Jaekwon
Thiele Dennis J
Herskowitz Ira
References (36)
36 references, click to expand
  1. Delivering copper inside yeast and human cells.
    Science. 1997 Oct 31;278(5339):817-8 PMID: 9381192
  2. Two nuclear proteins, Cin5 and Ydr259c, confer resistance to cisplatin in Saccharomyces cerevisiae.
    Mol Pharmacol. 2001 Mar;59(3):470-4 PMID: 11179441
  3. Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis.
    EMBO J. 1996 Jul 15;15(14):3515-23 PMID: 8670854
  4. Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant.
    Gene. 2000 Aug 22;254(1-2):87-96 PMID: 10974539
  5. Copper-specific transcriptional repression of yeast genes encoding critical components in the copper transport pathway.
    J Biol Chem. 1997 Jun 20;272(25):15951-8 PMID: 9188496
  6. Increased sensitivity of UV-repair-deficient human cells to DNA bound platinum products which unlike thymine dimers are not recognized by an endonuclease extracted from Micrococcus luteus.
    Mutat Res. 1978 Jul;51(1):121-32 PMID: 672924
  7. A genome-wide screening in Saccharomyces cerevisiae for genes that confer resistance to the anticancer agent cisplatin.
    Biochem Biophys Res Commun. 2000 Mar 24;269(3):767-74 PMID: 10720490
  8. Ixr1, a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin.
    Science. 1993 Jul 30;261(5121):603-5 PMID: 8342024
  9. SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line.
    Cancer Res. 2001 Oct 1;61(19):6982-6 PMID: 11585720
  10. A widespread transposable element masks expression of a yeast copper transport gene.
    Genes Dev. 1996 Aug 1;10(15):1917-29 PMID: 8756349
  11. Effect of cis-platinum(II)diamminodichloride on wild type and deoxyribonucleic acid repair deficient mutants of Escherichia coli.
    J Bacteriol. 1973 Dec;116(3):1247-52 PMID: 4584807
  12. Loss of DNA mismatch repair due to knockout of MSH2 or PMS2 results in resistance to cisplatin and carboplatin.
    Int J Oncol. 1997 Sep;11(3):539-42 PMID: 21528244
  13. Drugs five years later. Cisplatin.
    Ann Intern Med. 1984 May;100(5):704-13 PMID: 6370067
  14. Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae.
    J Biol Chem. 1998 Sep 11;273(37):23716-21 PMID: 9726978
  15. Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance.
    Biochem Biophys Res Commun. 1995 Nov 2;216(1):258-64 PMID: 7488097
  16. Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1.
    J Biol Chem. 1997 Jul 11;272(28):17711-8 PMID: 9211922
  17. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development.
    Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6842-7 PMID: 11391005
  18. The Fe(II) permease Fet4p functions as a low affinity copper transporter and supports normal copper trafficking in Saccharomyces cerevisiae.
    Biochem J. 2000 Oct 15;351 Pt 2:477-84 PMID: 11023834
  19. Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue.
    J Biol Chem. 1995 Nov 24;270(47):28479-86 PMID: 7499355
  20. Cellular accumulation of the anticancer agent cisplatin: a review.
    Br J Cancer. 1993 Jun;67(6):1171-6 PMID: 8512802
  21. Large-scale analysis of gene expression, protein localization, and gene disruption in Saccharomyces cerevisiae.
    Genes Dev. 1994 May 1;8(9):1087-105 PMID: 7926789
  22. Nucleotide-excision repair of DNA in cell-free extracts of the yeast Saccharomyces cerevisiae.
    Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):4907-11 PMID: 8506335
  23. Cisplatin and DNA repair in cancer chemotherapy.
    Trends Biochem Sci. 1995 Oct;20(10):435-9 PMID: 8533159
  24. The Saccharomyces cerevisiae copper transport protein (Ctr1p). Biochemical characterization, regulation by copper, and physiologic role in copper uptake.
    J Biol Chem. 1994 Oct 14;269(41):25660-7 PMID: 7929270
  25. Biochemical characterization of the human copper transporter Ctr1.
    J Biol Chem. 2002 Feb 8;277(6):4380-7 PMID: 11734551
  26. MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast.
    EMBO J. 1993 Dec 15;12(13):5051-6 PMID: 8262047
  27. Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2).
    FEBS Lett. 1999 Aug 6;456(2):327-31 PMID: 10456333
  28. Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae.
    Yeast. 1998 Jul;14(10):953-61 PMID: 9717241
  29. A series of protein phosphatase gene disruptants in Saccharomyces cerevisiae.
    Yeast. 1999 Nov;15(15):1669-79 PMID: 10572263
  30. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport.
    Cell. 1994 Jan 28;76(2):393-402 PMID: 8293472
  31. Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation.
    Biochemistry. 1985 Jan 29;24(3):707-13 PMID: 4039603
  32. Reactions of the UVRABC excision nuclease with DNA damaged by diamminedichloroplatinum(II).
    Nucleic Acids Res. 1985 Oct 25;13(20):7395-412 PMID: 3903663
  33. The HMG-domain protein Ixr1 blocks excision repair of cisplatin-DNA adducts in yeast.
    Mutat Res. 1996 Jan 2;362(1):75-86 PMID: 8538651
  34. Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance.
    Cancer Res. 2000 Mar 1;60(5):1312-6 PMID: 10728692
  35. hCTR1: a human gene for copper uptake identified by complementation in yeast.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7481-6 PMID: 9207117
  36. Clinical perspectives on platinum resistance.
    Drugs. 2000;59 Suppl 4:9-17; discussion 37-8 PMID: 10864226
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.162491399
Published
2002-10-29
Epub
2002-00-07
Pages
14298-302
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC137878
Subset
IM
Grants
NIGMS NIH HHS · GM41840 · United States
NIGMS NIH HHS · R01 GM041840 · United States
NIGMS NIH HHS · GM62555 · United States
NIGMS NIH HHS · GM61390 · United States
NIGMS NIH HHS · U01 GM061390 · United States
NIGMS NIH HHS · U19 GM061390 · United States
NIGMS NIH HHS · R01 GM062555 · United States
Corrections
CommentIn
PMID: 12391309
External Links
PubMed source DOI: 10.1073/pnas.162491399 PMC Full Text View journal details
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