The copper influx transporter human copper transport protein 1 regulates the uptake of cisplatin in human ovarian carcinoma cells.
نویسندگان
چکیده
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 microM 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.
منابع مشابه
The copper influx transporter hCTR1 regulates the uptake of cisplatin in human ovarian carcinoma cells
متن کامل
Cisplatin rapidly down-regulates its own influx transporter hCTR1 in cultured human ovarian carcinoma cells.
PURPOSE Cisplatin (DDP)-resistant cells commonly exhibit reduced drug accumulation. Previous studies have shown that the major copper (Cu) influx transporter CTR1 controls the uptake of DDP in yeast and mammalian cells. The goal of this study was to examine the effect of Cu and DDP on the level and subcellular localization of hCTR1 protein in human ovarian carcinoma cells. EXPERIMENTAL DESIGN...
متن کاملThe internalization and degradation of human copper transporter 1 following cisplatin exposure.
The human copper transporter 1 (hCTR1), the major transporter responsible for copper influx, mediates one component of the cellular accumulation of cisplatin (DDP). Both copper and DDP cause rapid down-regulation of hCTR1 expression in human ovarian carcinoma cells. In this study, we investigated the mechanism of this effect using digital deconvolution microscopy and Western blot analysis of ce...
متن کاملCopper transporter 2 regulates the cellular accumulation and cytotoxicity of Cisplatin and Carboplatin.
PURPOSE Copper transporter 2 (CTR2) is known to mediate the uptake of Cu(+1) by mammalian cells. Several other Cu transporters, including the influx transporter CTR1 and the two efflux transporters ATP7A and ATP7B, also regulate sensitivity to the platinum-containing drugs. We sought to determine the effect of CTR2 on influx, intracellular trafficking, and efflux of cisplatin and carboplatin. ...
متن کاملEnhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1.
PURPOSE The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs. However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hC...
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ورودعنوان ژورنال:
- Molecular pharmacology
دوره 66 4 شماره
صفحات -
تاریخ انتشار 2004