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The Internalization and Degradation of Human Copper Transporter 1 following Cisplatin Exposure

Department of Medicine and the Rebecca and John Moores Cancer Center, University of California at San Diego, La Jolla, California

Requests for reprints: Stephen B. Howell, Department of Medicine and the Rebecca and John Moores Cancer Center, University of California at San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819. Phone: 858-822-1110; Fax: 858-822-1111; E-mail: showell{at}ucsd.edu.

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 cells stained with antibodies directed at both ends of the protein. Treatment of 2008 cells with DDP in combination with inhibitors of various endosomal pathways (amiloride, cytochalasin D, nystatin, and methyl-ß-cyclodextrin) showed that hCTR1 degradation was blocked by amiloride and cytochalasin D, indicating that hCTR1 was internalized primarily by macropinocytosis. Expression of transdominant-negative forms of dynamin I and Rac showed that loss of hCTR1 was not dependent on pathways regulated by either of these proteins. DDP-induced loss of hCTR1 was blocked by the proteasome inhibitors lactacystin, proteasome inhibitor 1, and MG132. This study confirms that DDP triggers the rapid loss of hCTR1 from ovarian carcinoma cells at clinically relevant concentrations. The results indicate that DDP-induced loss of hCTR1 involves internalization from the plasma membrane by macropinocytosis followed by proteasomal degradation. Because hCTR1 is a major determinant of early DDP uptake, prevention of its degradation offers a potential approach to enhancing tumor sensitivity. (Cancer Res 2006; 66(22): 10944-52)

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