Regulation of the Export of Platinum-Containing Drugs by the Copper Efflux Transporters ATP7A and ATP7B
Abstract
ATP7A and ATP7B are P-type ATPases that detoxifie copper (Cu) through sequestration into the secretory pathway. While ATP7A is ubiquitously expressed, the expression of ATP7B is mainly specific to the liver tissue. These transporters are up-regulated in many types of tumors refractory, to the platinum-(Pt) containing drugs. Studies on cell lines indicate that ATP7A and ATP7B mediate sequestration and efflux of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP). An in vitro transport assay system consisting of vesicles isolated from Sf9 cells that expressed either a wild type ATP7B (WT) or a mutant form of this protein (MT) was used to determine whether ATP7B plays a direct role in the transport of DDP. While both forms of ATP7B significantly enhanced the capacity of Sf9 vesicles to bind DDP in the absence of ATP, only the WT form was capable of mediating ATP-dependent accumulation of DDP and forming a transient acylphosphate inter me diate in the presence of DDP. ATP7B-mediated transport of DDP into Sf9 vesicles was similar to that for 64Cu, but had a slower rate. DDP and Cu also inhibited each other's transport into the WT-expressing vesicles. These studies demonstrated that, although less effective than Cu, DDP serves as a substrate of ATP7B.
Keywords
ATP7A ATP7B P-type ATPase Copper homeostasis CisplatinNotes
Acknowledgments
The work reviewed in this paper was supported by the NIH grant CA78648-08 and a grant from the Clayton Medical Research Foundation. The production of 64Cu at Washington University School of Medicine was supported by the National Cancer Institute grant R24-CA86307.
References
- 1.Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM. The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 2008;48:495–535.PubMedCrossRefGoogle Scholar
- 2.Safaei R, Howell SB. Regulation of the cellular pharmacology and cytotoxicity of cisplatin by copper transporters. In: Beverly A. Teicher PD, eds. Cancer Drug Discovery and Development. Totowa, New Jersey, US: Humana Press, 2006:309–27.Google Scholar
- 3.Pena MM, Lee J, Thiele DJ. A delicate balance: homeostatic control of copper uptake and distribution. J Nutr 1999;129:1251–60.PubMedGoogle Scholar
- 4.Solioz M, Vulpe C. CPx-type ATPases: a class of p-type ATPases that pump heavy metals. Trends Biochem Sci 1996;21:237–41.PubMedGoogle Scholar
- 5.Mercer JFB, Camakaris J. Menkes and Wilson's diseases: genetic disorders of copper transport. New York, US: Chapman and Hall, 1997.Google Scholar
- 6.Lockhart PJ, La Fontaine S, Firth SD, Greenough M, Camakaris J, Mercer JF. Correction of the copper transport defect of Menkes patient fibroblasts by expression of two forms of the sheep Wilson ATPase. Biochim Biophys Acta 2002;1588:189–94.PubMedCrossRefGoogle Scholar
- 7.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 2005;280:9640–5.PubMedCrossRefGoogle Scholar
- 8.Niciu MJ, Ma XM, El Meskini R, Pachter JS, Mains RE, Eipper BA. Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease. Neurobiol Dis 2007;27:278–91.PubMedCrossRefGoogle Scholar
- 9.Linz R, Barnes NL, Zimnicka AM, Kaplan JH, Eipper B, Lutsenko S. The intracellular targeting of copper-transporting ATPase ATP7a in a normal and ATP7b-/- kidney. Am J Physiol Renal Physiol 2007;294:F53–61.PubMedCrossRefGoogle Scholar
- 10.Samimi G, Katano K, Holzer AK, Safaei R, Howell SB. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol 2004; 66:25–32.PubMedCrossRefGoogle Scholar
- 11.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 2004;10:4661–9.PubMedCrossRefGoogle Scholar
- 12.Samimi G, Varki NM, Wilczynski S, Safaei R, Alberts DS, Howell SB. Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 2003;9:5853–9.PubMedGoogle Scholar
- 13.Komatsu M, Sumizawa T, Mutoh M, et al. Copper-transporting P-type adenosine triphos-phatase (ATP7B) is associated with cisplatin resistance. Cancer Res 2000;60:1312–6.PubMedGoogle Scholar
- 14.Katano K, Safaei R, Samimi G, Holzer A, Rochdi M, Howell SB. The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells. Mol Pharmacol 2003;64:466–73.PubMedCrossRefGoogle Scholar
- 15.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 2004;10:4578–88.PubMedCrossRefGoogle Scholar
- 16.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 2002;62:6559–65.PubMedGoogle Scholar
- 17.Safaei R. Role of copper transporters in the uptake and efflux of platinum containing drugs. Cancer Lett 2006;234:34–9.PubMedCrossRefGoogle Scholar
- 18.Safaei R, Otani S, Larson BJ, Rasmussen ML, Howell SB. Transport of cisplatin by the copper efflux transporter ATP7B. Mol Pharmacol 2007; 73:461–8.PubMedCrossRefGoogle Scholar
- 19.Lin X, Okuda T, Holzer A, Howell SB. The copper transporter CTR1 regulates cisplatin uptake inSaccharomyces cerevisiae. Mol Pharmacol 2002;62:1154–9.PubMedCrossRefGoogle Scholar
- 20.Safaei R, Katano K, Samimi G, et al. Cross-resistance to cisplatin in cells with acquired resistance to copper. Cancer Chemother Pharmacol 2004;53:239–46.PubMedCrossRefGoogle Scholar