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PMID: 12644836 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines.

British journal of cancer ·Vol. 88 ·No. 6 ·2003-03-24 ·Pages 951-6

Okuno S, Sato H, Kuriyama-Matsumura K, Tamba M, Wang H, Sohda S, Hamada H, Yoshikawa H, Kondo T, Bannai S

Abstract

Transport system x(c)(-) is a member of plasma membrane heterodimeric amino-acid transporters and consists of two protein components, xCT and 4F2hc. This system mediates cystine entry coupled with the exodus of intracellular glutamate and regulates the intracellular glutathione (GSH) levels in most mammalian cultured cells. We studied the activity of system x(c)(-) and GSH content in human ovarian cancer cell line (A2780) and its cisplatin (CDDP)-resistant variant (A2780DDP). The rate of cystine uptake was approximately 4.5-fold higher in A2780DDP cells than in A2780 cells and the cystine uptake in A2780DDP cells was mediated by system x(c)(-). Intracellular GSH content was much higher in A2780DDP cells but it fell drastically in the presence of excess glutamate, which inhibited the cystine uptake competitively. xCT and 4F2hc mRNAs were definitely expressed in A2780DDP cells, but far less in A2780 cells. Expression of system x(c)(-) activity by transfection with cDNAs for xCT and 4F2hc made A2780 cells more resistant to CDDP. Similar results on the cystine uptake were obtained in human colonic cancer cell lines. These findings suggest that the system x(c)(-) plays an important role in maintaining the higher levels of GSH and consequently in CDDP resistance in cancer cell lines.

MeSH Terms

Amino Acid Transport Systems Antineoplastic Agents/pharmacology Cisplatin/pharmacology Colonic Neoplasms/pathology Cystine/pharmacokinetics DNA, Complementary Drug Resistance, Neoplasm Female Glutathione/pharmacology Humans Ovarian Neoplasms/pathology Transfection Tumor Cells, Cultured

Chemicals

Amino Acid Transport Systems Antineoplastic Agents DNA, Complementary Cystine Glutathione Cisplatin

Authors & Affiliations

10 authors, click to expand affiliations / ORCID

Okuno S

Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Sato H

Kuriyama-Matsumura K

Tamba M

Wang H

Sohda S

Hamada H

Yoshikawa H

Kondo T

Bannai S

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Article Info

Journal

British journal of cancer

Abbr.

Br J Cancer

ISSN

0007-0920

DOI

10.1038/sj.bjc.6600786

Published

2003-03-24

Pages

951-6

Language

English

Region

England

NLM ID

0370635

PMCID

PMC2377069

Subset

External Links

PubMed source DOI: 10.1038/sj.bjc.6600786 PMC Full Text View journal details

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Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines.

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