The Copper Influx Transporter Human Copper Transport Protein 1 Regulates the Uptake of Cisplatin in Human Ovarian Carcinoma Cells

Holzer, Alison K.; Samimi, Goli; Katano, Kuniyuki; Naerdemann, Wiltrud; Lin, Xi Zhang; Safaei, Roohangiz; Howell, Stephen B.

doi:10.1124/mol.104.001198

Cited by 200 publications

(140 citation statements)

References 24 publications

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“…Transporters demonstrating changes in our hypoxia model include SLC28A2, SLC29A1, SLC31A1 and SLC19A1 have also been shown to be essential for chemosensitivity of drugs such as gemcitabine, cisplatin and methotrexate, respectively. [35][36][37] Therefore, these findings suggest that regulatory changes in ABC and SLC transporter expression within hypoxic breast cancer cells may contribute to differences in chemosensitivity and chemoresistance within hypoxic cells. Furthermore, altered expression during hypoxic stress may be an essential adaptation to maintain transport of nutrients and cofactors to support energy production and biosynthesis.…”

Section: Resultsmentioning

confidence: 98%

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Sweet

Paul²,

Zastre³

2010

Cancer Biology & Therapy

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Section: Resultsmentioning

confidence: 98%

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Sweet

Paul²,

Zastre³

2010

Cancer Biology & Therapy

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“…Fixed and paraffin-embedded cell blocks were prepared from human ovarian carcinoma A2780 cells and the A2780/hCTR1 subline that had been stably transfected with an hCTR1 expression vector (Holzer et al 2004b). As shown in Figure 1A, A2780 cells expressed a moderate level of hCTR1, and staining was blocked by coincubation of the antibody with the peptide that was used as the immunogen.…”

Section: Resultsmentioning

confidence: 99%

Expression of the Human Copper Influx Transporter 1 in Normal and Malignant Human Tissues

Holzer

Varki

et al. 2006

J Histochem Cytochem.

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The major copper influx transporter, copper transporter 1 (hCTR1), controls the cellular accumulation of cisplatin in mammalian cells. The goal of this study was to determine the pattern of hCTR1 expression in normal and malignant human tissues. Tissue arrays were stained with an antibody specific for hCTR1 using standard immunohistochemical techniques. Particularly strong staining was noted in the α cells of the pancreatic islets, enteroendocrine cells of the gastric mucosa and bronchioles, C cells of the thyroid, and a subset of cells in the anterior pituitary. Frequency and intensity of hCTR1 staining in malignant tissues reflected the levels found in their normal tissue counterparts. For example, neither normal prostate nor prostate cancers expressed hCTR1, whereas it was commonly expressed in both normal colonic epithelium and in colon carcinomas. Strong staining was observed in a limited number of cases of carcinoid tumors, Ewing's sarcoma, and undifferentiated carcinomas. Although all tissues require copper, expression of hCTRI was highly variable among normal tissues and among the major human malignancies, with the highest levels found in enteroendocrine cells. No hCTR1 expression was found in several common types of cancer, suggesting that hCTR1 expression is not commonly enhanced by transformation.

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“…DDP resistance is often accompanied by cross-resistance to copper and vice versa (7,8). We (9,10) and others (11,12) have shown that the major plasma membrane copper influx transporter, copper transporter 1 (CTR1), is responsible for a substantial portion of the DDP influx in both yeast and mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

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

2006

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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-B-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 DDPinduced 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.

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The Copper Influx Transporter Human Copper Transport Protein 1 Regulates the Uptake of Cisplatin in Human Ovarian Carcinoma Cells

Cited by 200 publications

References 24 publications

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Expression of the Human Copper Influx Transporter 1 in Normal and Malignant Human Tissues

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

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