The Copper Influx Transporter Human Copper Transport Protein 1 Regulates the Uptake of Cisplatin in Human Ovarian Carcinoma Cells
Cells selected for resistance to cisplatin are often cross-resistant to copper and vice versa, and the major copper influx transporter copper transport protein 1 (CTR1) has been shown to regulate the uptake of cisplatin, carboplatin, and oxaliplatin in yeast. To further define the role of hCTR1 in h...
Saved in:
Published in | Molecular pharmacology Vol. 66; no. 4; pp. 817 - 823 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.10.2004
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Cells selected for resistance to cisplatin are often cross-resistant to copper and vice versa, and the major copper influx
transporter copper transport protein 1 (CTR1) has been shown to regulate the uptake of cisplatin, carboplatin, and oxaliplatin
in yeast. To further define the role of hCTR1 in human tumor cells, the ovarian carcinoma cell line A2780 was molecularly
engineered to increase expression of hCTR1 by a factor of 20-fold. Enhanced expression of hCTR1 in the A2780/hCTR1 cells was
associated with a 6.5-fold increase in basal steady-state copper content and a 13.7-fold increase in initial copper influx,
demonstrating that the exogenously expressed hCTR1 was functional in altering copper homeostasis. The A2780/hCTR1 cells accumulated
46% more platinum after a 1-h exposure to 2 μM cisplatin, and 55% more after a 24 h exposure, than the control A2780/empty
vector cells. The initial uptake of cisplatin was 81% higher in the A2780/hCTR1 cells when measured at 5 min. Thus, increased
expression of hCTR1 had a substantially larger effect on the cellular pharmacology of copper than cisplatin. Interestingly,
the increased uptake of copper and cisplatin was accompanied by only a marginal increase in sensitivity to the cytotoxic effect
of copper and cisplatin, and there was no increase in the extent of cisplatin-DNA adduct formation. Thus, although increased
expression of hCTR1 mediates greater cellular accumulation of copper and cisplatin, hCTR1 delivers these compounds into intracellular
compartments from which they do not have ready access to their key cytotoxic targets. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.104.001198 |