Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy

Lee, Yoo-Young; Choi, Chel Hun; Do, In‐Gu; Song, Sang Yong; Lee, Wooseok; Park, Hwang Shin; Song, Tae Jong; Kim, Min Kyu; Kim, Tae-Joong; Lee, Jeong‐Won; Bae, Duk-Soo; Kim, Byoung-Gie

doi:10.1016/j.ygyno.2011.04.025

Cited by 77 publications

(53 citation statements)

References 23 publications

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“…Similar to Cu ϩ , platinum binds to Met-rich motifs within the Ctr1 ectodomain (27), but studies using Ctr1 mutants that are defective in Cu ϩ transport, but competent for cisplatin acquisition, suggest that Ctr1 delivers platinum into cells via receptor-mediated endocytosis rather than acting as a membrane channel as it does for Cu ϩ (15,26). Cancer patient survival after treatment with platinum-based drugs is associated with high levels of CTR1 expression and lower CTR1 levels associated with decreased survival to cisplatin (62,63). Intriguingly, and in contrast to CTR1, low levels of CTR2 positively associate with patient survival after cisplatin therapy (63,64).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer patient survival after treatment with platinum-based drugs is associated with high levels of CTR1 expression and lower CTR1 levels associated with decreased survival to cisplatin (62,63). Intriguingly, and in contrast to CTR1, low levels of CTR2 positively associate with patient survival after cisplatin therapy (63,64). In agreement with this observation, cultured cells lacking Ctr2 exhibit increased whole-cell platinum accumulation (32,65).…”

Section: Discussionmentioning

confidence: 99%

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Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Öhrvik

Logeman

Turk

et al. 2016

Journal of Biological Chemistry

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Copper is an essential metal ion for embryonic development, iron acquisition, cardiac function, neuropeptide biogenesis, and other critical physiological processes. Ctr1 is a high affinity Cu ؉ transporter on the plasma membrane and endosomes that exists as a full-length protein and a truncated form of Ctr1 lacking the methionine-and histidine-rich metal-binding ectodomain, and it exhibits reduced Cu ؉ transport activity. Here, we identify the cathepsin L/B endolysosomal proteases functioning in a direct and rate-limiting step in the Ctr1 ectodomain cleavage. Cells and mice lacking cathepsin L accumulate full-length Ctr1 and hyper-accumulate copper. As Ctr1 also transports the chemotherapeutic drug cisplatin via direct binding to the ectodomain, we demonstrate that the combination of cisplatin with a cathepsin L/B inhibitor enhances cisplatin uptake and cell killing. These studies identify a new processing event and the key protease that cleaves the Ctr1 metal-binding ectodomain, which functions to regulate cellular Cu ؉ and cisplatin acquisition.Copper is essential for key biological processes, including electron transfer, iron acquisition, dopamine hydrolysis, and superoxide disproportionation, and defects in copper metabolism are associated with cardiomyopathy, anemia, peripheral neuropathy, and neutropenia (1-6). Although many proteins involved in the acquisition and intracellular distribution of copper have been identified, little is known about the regulation of copper import. The transport of Cu ϩ from the extracellular environment is accomplished by the evolutionarily conserved homotrimeric integral membrane protein, copper transporter 1 (Ctr1) (7-13), which resides on the plasma membrane and in endosomal compartments (14 -18). High affinity Cu ϩ import via Ctr1 requires a methionine-and histidine-rich metal-binding extracellular domain (ectodomain) that is thought to concentrate extracellular Cu ϩ near the ion trans-membrane pore (19 -23). Additionally, Ctr1 binds the chemotherapeutic agent cisplatin via the methionine ligands in the ectodomain and imports cisplatin and other platinum-based chemotherapeutic agents via an endocytic mechanism (24 -28). Despite a critical role for the Ctr1 ectodomain in both Cu ϩ and cisplatin import, both a full-length form and a truncated form of Ctr1 (tCtr1) 4 are present in cultured cells and tissues (18,29,30). The latter lacks the ectodomain and drives ϳ50% of the Cu ϩ uptake as compared with full-length Ctr1 (31).Previously, an integral membrane protein similar to Ctr1, denoted Ctr2, was shown to both interact with and regulate the ratio of full-length Ctr1 to tCtr1 in mouse embryonic fibroblasts (MEFs) and in specific tissues in Ctr2 knock-out mice (32). In the absence of Ctr2, MEFs possess dramatically lower levels of tCtr1, while simultaneously expressing high levels of full-length Ctr1 and accumulating Cu ϩ and cisplatin. A large fraction of the Cu ϩ accumulated in Ctr2 Ϫ/Ϫ MEFs and mouse tissues is found in endosomal compartments (32). The mechanism by which Ct...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Öhrvik

Logeman

Turk

et al. 2016

Journal of Biological Chemistry

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“…They suggested that hCTR1 expressions in malignant tissues reflect the levels found in their normal tissue counterparts-such as a 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 gland-and that hCTR1 expression was not commonly enhanced by transformation. Lee et al found a lower expression of CTR1 mRNA in 40 ovarian cancer cell samples against normal ovarian tissue by real-time PCR with statistically significant differences (19). Therefore, the hCTR1 expression may not be commonly enhanced or repressed by the cancer transformation process and influenced by a tissue counterpart of a cancer.…”

Section: Discussionmentioning

confidence: 99%

Detection of Increased ⁶⁴Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with ⁶⁴CuCl₂ in Human Breast Cancer Xenograft Model

et al. 2014

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Copper is an essential cofactor for a variety of biochemical processes including oxidative phosphorylation, cellular antioxidant activity, and elimination of free radicals. The copper transporter 1 is known to be involved in cellular uptake of copper ions. In this study, we evaluated the utility of human copper transporter 1 (hCTR1) gene as a new reporter gene for 64 Cu PET imaging. Methods: Human breast cancer cells (MDA-MB-231) were infected with a lentiviral vector constitutively expressing the hCTR1 gene under super cytomegalovirus promoter, and positive clones (MDA-MB-231-hCTR1) were selected. The expression of hCTR1 gene in MDA-MB-231-hCTR1 cells was measured by reverse transcription polymerase chain reaction, Western blot, and 64 Cu uptake assay. To evaluate the cytotoxic effects induced by hCTR1 expression, the dose-dependent cell survival rate after treatment with cisplatin (Cis-diaminedichloroplatinum (II) [CDDP]) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue dye exclusion. Small-animal PET images were acquired in tumorbearing mice from 2 to 48 h after an intravenous injection of 64 Cu.

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“…Recent findings point out at the involvement of copper transporter 1 (CTR1) in the uptake of the platinum drug [5,6]. The transporter appears to be clinically relevant, since high expression of CTR1 in patients with ovarian carcinoma was associated with good therapeutic response, while low levels of the protein lead to poor therapeutic outcome [7]. Deletion of CTR1 was reported to decrease cisplatin accumulation and to increase resistance in vitro and in vivo [8,9].…”

Section: Introductionmentioning

confidence: 99%

Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells

Kalayda

Wagner

Jaehde

2012

Journal of Inorganic Biochemistry

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Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy

Cited by 77 publications

References 23 publications

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Detection of Increased ⁶⁴Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with ⁶⁴CuCl₂ in Human Breast Cancer Xenograft Model

Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells

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Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy

Cited by 77 publications

References 23 publications

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Detection of Increased 64Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with 64CuCl2 in Human Breast Cancer Xenograft Model

Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells

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Detection of Increased ⁶⁴Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with ⁶⁴CuCl₂ in Human Breast Cancer Xenograft Model