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

Seiko Ishida, Jaekwon Lee, Dennis J. Thiele, Ira Herskowitz

Research output: Contribution to journalArticle

555 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14298-14302
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number22
DOIs
StatePublished - Oct 29 2002
Externally publishedYes

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Cisplatin
Copper
Mammals
Yeasts
Pharmaceutical Preparations
Fungal Proteins
Gene Dosage
Protein Transport
Proteins
Alleles
Cell Line

ASJC Scopus subject areas

  • General

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Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. / Ishida, Seiko; Lee, Jaekwon; Thiele, Dennis J.; Herskowitz, Ira.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 22, 29.10.2002, p. 14298-14302.

Research output: Contribution to journalArticle

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