We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Human copper transporters: mechanism, role in human diseases and therapeutic potential

    Arnab Gupta

    Department of Physiology, Johns Hopkins University, 725 N Wolfe Street, Hunterian 203, Baltimore, MD 21205, USA.

    &
    Svetlana Lutsenko

    † Author for correspondence

    Department of Physiology, Johns Hopkins University, 725 N Wolfe Street, Hunterian 203, Baltimore, MD 21205, USA.

    Published Online:https://doi.org/10.4155/fmc.09.84

    Normal copper homeostasis is essential for human growth and development. Copper deficiency, caused by genetic mutations, inadequate diet or surgical interventions, may lead to cardiac hypertrophy, poor neuronal myelination, blood vessel abnormalities and impaired immune response. Copper overload is associated with morphological and metabolic changes in tissues and, if untreated, eventual death. Recent reports also indicate that changes in the expression of copper transporters alter the sensitivity of cancer cells to major chemotherapeutic drugs, such as cisplatin, although the mechanism behind this important phenomenon remains unclear. This review summarizes current information on the molecular characteristics of copper transporters CTR1, CTR2, ATP7A and ATP7B, their roles in mammalian copper homeostasis and the physiological consequences of their inactivation. The mechanisms through which copper transporters may influence cell sensitivity to cisplatin are discussed. Regulation of human copper homeostasis has significant therapeutic potential and requires the detailed understanding of copper transport mechanisms.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Nelson KT, Prohaska JR. Copper deficiency in rodents alters dopamine β-mono-oxygenase activity, mRNA and protein level. Br. J. Nutr.102(1),18–28 (2008).
    • Johnson WT, Anderson CM. Cardiac cytochrome C oxidase activity and contents of subunits 1 and 4 are altered in offspring by low prenatal copper intake by rat dams. J. Nutr.138(7),1269–1273 (2008).
    • Zhou Z, Johnson WT, Kang YJ. Regression of copper-deficient heart hypertrophy: reduction in the size of hypertrophic cardiomyocytes. J. Nutr. Biochem.20(8),621–628 (2008).
    • Smith AD, Botero S, Levander OA. Copper deficiency increases the virulence of amyocarditic and myocarditic strains of coxsackievirus B3 in mice. J. Nutr.138(5),849–855 (2008).
    • Gambling L, Andersen HS, McArdle HJ. Iron and copper, and their interactions during development. Biochem. Soc. Trans.36(6),1258–1261 (2008).
    • Keen CL, Uriu-Hare JY, Hawk SN et al. Effect of copper deficiency on prenatal development and pregnancy outcome. Am. J. Clin. Nutr.67(Suppl. 5),S1003–S1011 (1998).
    • Kaler SG, Holmes CS, Goldstein DS et al. Neonatal diagnosis and treatment of Menkes disease. N. Engl. J. Med.358(6),605–614 (2008).
    • de Luis DA, Pacheco D, Izaola O, Terroba MC, Cuellar L, Martin T. Clinical results and nutritional consequences of biliopancreatic diversion: three years of follow-up. Ann. Nutr. Metab.53(3–4),234–239 (2008).
    • Ernst B, Thurnheer M, Schmid SM, Schultes B. Evidence for the necessity to systematically assess micronutrient status prior to bariatric surgery. Obes. Surg.19(1),66–73 (2009).
    • 10  Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ. Hematological manifestations of copper deficiency: a retrospective review. Eur. J. Haematol.80(6),523–531 (2008).
    • 11  Marinella MA. Anemia following Roux-en-Y surgery for morbid obesity: a review. South Med. J.101(10),1024–1031 (2008).
    • 12  Halfdanarson TR, Kumar N, Hogan WJ, Murray JA. Copper deficiency in celiac disease. J. Clin. Gastroenterol.43(2),162–164 (2009).
    • 13  Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin. Proc.81(10),1371–1384 (2006).
    • 14  Das SK, Ray K. Wilson’s disease: an update. Nat. Clin. Pract. Neurol.2(9),482–493 (2006)
    • 15  Komatsu M, Sumizawa T, Mutoh M et al. Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res.60(5),1312–1316 (2000).
    • 16  Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit. Rev. Oncol. Hematol.53(1),13–23 (2005).
    • 17  Lim CM, Cater MA, Mercer JF, La Fontaine S. Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A. J. Biol. Chem.281(20),14006–14014 (2006).
    • 18  Holloway ZG, Grabski R, Szul T et al. Activation of ADP-ribosylation factor regulates biogenesis of the ATP7A-containing trans-Golgi network compartment and its Cu-induced trafficking. Am. J. Physiol. Cell Physiol.293(6),C1753–C1767 (2007).
    • 19  Burkhead JL, Morgan CT, Shinde U, Haddock G, Lutsenko S. COMMD1 forms oligomeric complexes targeted to the endocytic membranes via specific interactions with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem.284(1),696–707 (2009).
    • 20  Kim BE, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat. Chem. Biol.4(3),176–185 (2008).
    • 21  Maryon EB, Molloy SA, Zimnicka AM, Kaplan JH. Copper entry into human cells: progress and unanswered questions. Biometals20(3–4),355–364 (2007).
    • 22  Dancis A, Yuan DS, Haile D et al. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell76(2),393–402 (1994).
    • 23  Zhou B, Gitschier J. hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc. Natl Acad. Sci. USA94(14),7481–7486 (1997).
    • 24  Moller LB, Petersen C, Lund C, Horn N. Characterization of the hCTR1gene: genomic organization, functional expression, and identification of a highly homologous processed gene. Gene257(1),13–22 (2000).
    • 25  Kuo YM, Zhou B, Cosco D, Gitschier J. The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc. Natl Acad. Sci. USA98(12),6836–6841 (2001).
    • 26  Kuo YM, Gybina AA, Pyatskowit JW, Gitschier J, Prohaska JR. Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J. Nutr.136(1),21–26 (2006).
    • 27  Lee J, Pena MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J. Biol. Chem.277(6),4380–4387 (2002).▪ This study provided the first characterization of transport characteristics of CTR1 and identified silver as a specific inhibitor.
    • 28  Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system. J. Biol. Chem.277(43),40253–40259 (2002).
    • 29  Kim H, Son HY, Bailey SM, Lee J. Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis. Am J. Physiol. Gastrointest. Liver Physiol.296(2),G356–G364 (2009).
    • 30  Lee J, Prohaska JR, Thiele DJ. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc. Natl Acad. Sci. USA98(12),6842–6847 (2001).
    • 31  Haremaki T, Fraser ST, Kuo YM, Baron MH, Weinstein DC. Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation. Proc. Natl Acad. Sci. USA104(29),12029–12034 (2007).
    • 32  Nose Y, Kim BE, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab.4(3),235–244 (2006).▪▪ Pioneering experiments on tissue-specific inactivation of CTR1 that demonstrated the important role of CTR1 in intestinal absorption and revealed the unexpected function of intestinal CTR1 in mediating availability of absorbed copper to cytosolic proteins.
    • 33  Zimnicka AM, Maryon EB, Kaplan JH. Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis. J. Biol. Chem.282(36),26471–26480 (2007).▪▪ First demonstration that CTR1 may function in copper uptake at the blood site of various cells.
    • 34  Zerounian NR, Redekosky C, Malpe R, Linder MC. Regulation of copper absorption by copper availability in the Caco-2 cell intestinal model. Am. J. Physiol. Gastrointest. Liver Physiol.284(5),G739–G747 (2003)
    • 35  Guo Y, Smith K, Lee J, Thiele DJ, Petris MJ. Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter. J. Biol. Chem.279(17),17428–17433 (2004).
    • 36  Guo Y, Smith K, Petris MJ. Cisplatin stabilizes a multimeric complex of the human Ctr1 copper transporter: requirement for the extracellular methionine-rich clusters. J. Biol. Chem.279(45),46393–46399 (2004).
    • 37  Eisses JF, Kaplan JH. The mechanism of copper uptake mediated by human CTR1: a mutational analysis. J. Biol. Chem.280(44),37159–37168 (2005).
    • 38  De Feo CJ, Aller SG, Unger VM. A structural perspective on copper uptake in eukaryotes. Biometals20(3–4),705–716 (2007).
    • 39  Maryon EB, Molloy SA, Kaplan JH. O-linked glycosylation at threonine 27 protects the copper transporter hCTR1 from proteolytic cleavage in mammalian cells. J. Biol. Chem.282(28),20376–20387 (2007).
    • 40  Jiang J, Nadas IA, Kim MA, Franz KJ. A Mets motif peptide found in copper transport proteins selectively binds Cu(I) with methionine-only coordination. Inorg. Chem.44(26),9787–9794 (2005).
    • 41  De Feo CJ, Aller SG, Siluvai GS, Blackburn NJ, Unger VM. Three-dimensional structure of the human copper transporter hCTR1. Proc. Natl Acad. Sci. USA106(11),4237–4242 (2009).▪▪ Structural study offering important insights into the mechanism of copper entry into human cells.
    • 42  Puig S, Lee J, Lau M, Thiele DJ. Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J. Biol. Chem.277(29),26021–26030 (2002).
    • 43  Eisses JF, Kaplan JH. Molecular characterization of hCTR1, the human copper uptake protein. J. Biol. Chem.277(32),29162–29171 (2002).
    • 44  Sinani D, Adle DJ, Kim H, Lee J. Distinct mechanisms for Ctr1-mediated copper and cisplatin transport. J. Biol. Chem.282(37),26775–26785 (2007).
    • 45  Wu X, Sinani D, Kim H, Lee J. Copper transport activity of yeast Ctr1 is down-regulated via its C terminus in response to excess copper. J. Biol. Chem.284(7),4112–4122 (2009).
    • 46  Xiao Z, Wedd AG. A C-terminal domain of the membrane copper pump Ctr1 exchanges copper(I) with the copper chaperone Atx1. Chem. Commun. (Camb.)6,588–589 (2002).
    • 47  Chen HH, Song IS, Hossain A et al. Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol. Pharmacol.74(3),697–704 (2008).▪ Important study demonstrating the link between glutathione biosynthesis, CTR1 expression and resistance of cells to cisplatin.
    • 48  Gybina AA, Prohaska JR. Variable response of selected cuproproteins in rat choroid plexus and cerebellum following perinatal copper deficiency. Genes Nutr.1(1),51–59 (2006).
    • 49  Klomp AE, Tops BB, Van Denberg IE, Berger R, Klomp LW. Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem. J.364(2),497–505 (2002).
    • 50  van den Berghe PV, Folmer DE, Malingre HE et al. Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake. Biochem. J.407(1),49–59 (2007).
    • 51  Bertinato J, Swist E, Plouffe LJ, Brooks SP, L’Abbe MR. Ctr2 is partially localized to the plasma membrane and stimulates copper uptake in COS-7 cells. Biochem. J.409(3),731–740 (2008).
    • 52  Rees EM, Thiele DJ. Identification of a vacuole-associated metalloreductase and its role in Ctr2-mediated intracellular copper mobilization. J. Biol. Chem.282(30),21629–21638 (2007)
    • 53  Nyasae L, Bustos R, Braiterman L, Eipper B, Hubbard A. Dynamics of endogenous ATP7A (Menkes protein) in intestinal epithelial cells: copper-dependent redistribution between two intracellular sites. Am. J. Physiol. Gastrointest. Liver Physiol.292(4),G1181–G1194 (2007)▪ This study offers convincing evidence for a predominantly intracellular localization and, hence, function of ATP7A.
    • 54  Pase L, Voskoboinik I, Greenough M, Camakaris J. Copper stimulates trafficking of a distinct pool of the Menkes copper ATPase (ATP7A) to the plasma membrane and diverts it into a rapid recycling pool. Biochem. J.378(3),1031–1037 (2004).
    • 55  Schlief ML, Craig AM, Gitlin JD. NMDA receptor activation mediates copper homeostasis in hippocampal neurons J. Neurosci.25(1),239–246 (2005).
    • 56  Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD. Mechanisms of copper incorporation into human ceruloplasmin. J. Biol. Chem.277(48),46632–46638 (2002).
    • 57  Qin Z, Itoh S, Jeney V, Ushio-Fukai M, Fukai T. Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. Faseb. J.20(2),334–336 (2006).
    • 58  di Patti MC, Maio N, Rizzo G et al. Dominant mutants of ceruloplasmin impair the copper loading machinery in aceruloplasminemia. J. Biol. Chem.284(7),4545–4554 (2009)▪ The first direct demonstration of a tight functional link between copper transporter and acceptor protein.
    • 59  Stephenson SE, Dubach D, Lim CM, Mercer JF, La Fontaine S. A single PDZ domain protein interacts with the Menkes copper ATPase, ATP7A. A new protein implicated in copper homeostasis. J. Biol. Chem.280(39),33270–33279 (2005).
    • 60  Francis MJ, Jones EE, Levy ER, Martin RL, Ponnambalam S, Monaco AP. Identification of a di-leucine motif within the C terminus domain of the Menkes disease protein that mediates endocytosis from the plasma membrane. J. Cell Sci.112(11),1721–1732 (1999).
    • 61  Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J. Biol. Chem.280(10),9640–9645 (2005).
    • 62  Kuhlbrandt W. Biology, structure and mechanism of P-type ATPases. Nat. Rev. Mol. Cell Biol.5(4),282–295 (2004).
    • 63  Hatori Y, Hirata A, Toyoshima C, Lewis D, Pilankatta R, Inesi G. Intermediate phosphorylation reactions in the mechanism of ATP utilization by the copper ATPase (CopA) of Thermotoga maritima. J. Biol. Chem.283(33),22541–22549 (2008).
    • 64  Leonhardt K, Gebhardt R, Mossner J, Lutsenko S, Huster D. Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug. J. Biol. Chem.284(12),7793–7802 (2009).
    • 65  Walker JM, Huster D, Ralle M, Morgan CT, Blackburn NJ, Lutsenko S. The N-terminal metal-binding site 2 of the Wilson’s disease protein plays a key role in the transfer of copper from Atox1. J. Biol. Chem.279(15),15376–15384 (2004).
    • 66  Achila D, Banci L, Bertini I, Bunce J, Ciofi-Baffoni S, Huffman DL. Structure of human Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake. Proc. Natl Acad. Sci. USA103(15),5729–5734 (2006).
    • 67  Gonzalez-Guerrero M, Arguello JM. Mechanism of Cu+-transporting ATPases: soluble Cu+ chaperones directly transfer Cu+ to transmembrane transport sites. Proc. Natl Acad. Sci. USA105(16),5992–5997 (2008).
    • 68  Huster D, Lutsenko S. The distinct roles of the N-terminal copper-binding sites in regulation of catalytic activity of the Wilson’s disease protein. J. Biol. Chem.278(34),32212–32218 (2003).
    • 69  Linz R, Lutsenko S. Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. J. Bioenerg. Biomembr.39(5–6),403–407 (2007).
    • 70  Monty JF, Llanos RM, Mercer JF, Kramer DR. Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice. J. Nutr.135(12),2762–2766 (2005).
    • 71  Greenough M, Pase L, Voskoboinik I, Petris MJ, O’Brien AW, Camakaris J. Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells. Am. J. Physiol. Cell Physiol.287(5),C1463–C1471 (2004).
    • 72  Roelofsen H, Wolters H, Van Luyn MJ, Miura N, Kuipers F, Vonk RJ. Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology119(3),782–793 (2000).
    • 73  Hardman B, Michalczyk A, Greenough M, Camakaris J, Mercer JF, Ackland ML. Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells. Biochem. J.402(2),241–250 (2007).
    • 74  Barnes N, Bartee MY, Braiterman L et al. Cell-specific trafficking suggests a new role for renal ATP7B in the intracellular copper storage. Traffic10(6),767–779 (2009).
    • 75  Weiss KH, Wurz J, Gotthardt D, Merle U, Stremmel W, Fullekrug J. Localization of the Wilson disease protein in murine intestine. J. Anat.213(3),232–240 (2008).
    • 76  Finney L, Mandava S, Ursos L et al. X-ray fluorescence microscopy reveals large-scale relocalization and extracellular translocation of cellular copper during angiogenesis. Proc. Natl Acad. Sci. USA104(7),2247–2252 (2007).
    • 77  Finney L, Vogt S, Fukai T, Glesne D. Copper and angiogenesis: unravelling a relationship key to cancer progression. Clin. Exp. Pharmacol. Physiol.36(1),88–94 (2009).
    • 78  Goodman VL, Brewer GJ, Merajver SD. Copper deficiency as an anti-cancer strategy. Endocr. Relat. Cancer11(2),255–263 (2004).
    • 79  Goodman VL, Brewer GJ, Merajver SD. Control of copper status for cancer therapy. Curr. Cancer Drug Targets5(7),543–549 (2005).
    • 80  Huster D, Purnat TD, Burkhead JL et al. High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease. J. Biol. Chem.282(11),8343–8355 (2007).▪ Demonstration of a specific effect of copper overload on lipid biosynthesis in the liver.
    • 81  Tang Z, Gasperkova D, Xu J, Baillie R, Lee JH, Clarke SD. Copper deficiency induces hepatic fatty acid synthase gene transcription in rats by increasing the nuclear content of mature sterol regulatory element binding protein 1. J. Nutr.130(12),2915–2921 (2000).
    • 82  Lang PA, Schenck M, Nicolay JP et al. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat. Med.13(2),164–170 (2007).
    • 83  Dunn TM, Haak D, Monaghan E, Beeler TJ. Synthesis of monohydroxylated inositolphosphorylceramide (IPC-C) in Saccharomyces cerevisiae requires Scs7p, a protein with both a cytochrome b5-like domain and a hydroxylase/desaturase domain. Yeast14(4),311–321 (1998).
    • 84  Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol.11(1),107–116 (2001).
    • 85  Itoh S, Kim HW, Nakagawa O et al. Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J. Biol. Chem.283(14),9157–9167 (2008).▪ Describes an intriguing mechanism through which changes in copper levels may alter cell proliferation.
    • 86  Donley SA, Ilagan BJ, Rim H, Linder MC. Copper transport to mammary gland and milk during lactation in rats. Am. J. Physiol. Endocrinol. Metab.283(4),E667–E675 (2002).
    • 87  Kelleher SL, Lonnerdal B. Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization. Am. J. Physiol. Regul. Integr. Comp. Physiol.291(4),R1181–R1191 (2006).
    • 88  Michalczyk A, Bastow E, Greenough M et al. ATP7B expression in human breast epithelial cells is mediated by lactational hormones. J. Histochem. Cytochem.56(4),389–399 (2008).
    • 89  Vanderwerf SM, Cooper MJ, Stetsenko IV, Lutsenko S. Copper specifically regulates intracellular phosphorylation of the Wilson’s disease protein, a human copper-transporting ATPase. J. Biol. Chem.276(39),36289–36294 (2001).
    • 90  Voskoboinik I, Fernando R, Veldhuis N et al. Protein kinase-dependent phosphorylation of the Menkes copper P-type ATPase. Biochem. Biophys. Res. Commun.303(1),337–342 (2003).
    • 91  White C, Kambe T, Fulcher YG et al. Copper transport into the secretory pathway is regulated by oxygen in macrophages. J. Cell. Sci.122(9),1315–1321 (2009).▪ Direct demonstration of a specific role for ATP7A in cell response to pathological conditions.
    • 92  Reedijk J. Why does Cisplatin reach Guanine-n7 with competing S-donor ligands available in the cell? Chem. Rev.99(9),2499–2510 (1999).
    • 93  Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev.33(1),9–23 (2007).
    • 94  Katano K, Kondo A, Safaei R et al. Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res.62(22),6559–6565 (2002).
    • 95  Ishida S, Lee J, Thiele DJ, Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc. Natl Acad. Sci. USA99(22),14298–14302 (2002).
    • 96  Rabik CA, Maryon EB, Kasza K, Shafer JT, Bartnik CM, Dolan ME. Role of copper transporters in resistance to platinating agents. Cancer Chemother. Pharmacol.64(1),133–142 (2008).
    • 97  Larson CA, Blair BG, Safaei R, Howell SB. The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol. Pharmacol.75(2),324–330 (2009).
    • 98  Blair BG, Larson CA, Safaei R, Howell SB. Copper transporter 2 regulates the cellular accumulation and cytotoxicity of cisplatin and carboplatin. Clin. Cancer Res.15(13),4312–4321 (2009).
    • 99  Samimi G, Safaei R, Katano K et al. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin. Cancer Res.10(14),4661–4669 (2004).
    • 100  Mangala LS, Zuzel V, Schmandt R et al. Therapeutic targeting of ATP7B: reversing cisplatin resistance in ovarian carcinoma. Cancer Res. Clin.15(11),3770–3780 (2009).▪ Direct demonstration in vivo of the therapeutic effect of ATP7B downregulation.
    • 101  Katano K, Safaei R, Samimi G et al. Confocal microscopic analysis of the interaction between cisplatin and the copper transporter ATP7B in human ovarian carcinoma cells. Clin. Cancer Res.10(13),4578–4588 (2004).▪ Important demonstration of a link between cellular copper homeostasis and resistance to cisplatin.
    • 102  Safaei R, Otani S, Larson BJ, Rasmussen ML, Howell SB. Transport of cisplatin by the copper efflux transporter ATP7B. Mol. Pharmacol.73(2),461–468 (2008).
    • 103  Dolgova NV, Olson D, Lutsenko S, Dmitriev OY. The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin. Biochem. J.419(1),51–56 (2009).
    • 104  Owatari S, Akune S, Komatsu M et al. Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer. Cancer Res.67(10),4860–4868 (2007).