Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals.
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.
Ishida
Seiko
S
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448, USA.
Lee
Jaekwon
J
Thiele
Dennis J
DJ
Herskowitz
Ira
I
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D027682:Cation Transport Proteins; D002460:Cell Line; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D000079923:Copper Transporter 1; D025141:Drug Resistance, Fungal / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D008322:Mammals; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
D000970:Antineoplastic Agents; C490078:CTR1 protein, S cerevisiae; D027682:Cation Transport Proteins; D003301:Copper Radioisotopes; D000079923:Copper Transporter 1; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C490077:Slc31a1 protein, mouse; D002945:Cisplatin