Expression of copper-transporting P-type adenosine triphosphatase in human esophageal carcinoma

Higashimoto, Masashi; Kanzaki, Atsuko; Shimakawa, Takeshi; Konno, Satoshi; Naritaka, Yoshihiko; Nitta, Yoshio; Mori, Shiro; Shirata, Shinobu; Yoshida, Ayumi; Terada, Kunihiko; Sugiyama, Toshihiro; Ogawa, Kenji; Takebayashi, Yuji

doi:10.3892/ijmm.11.3.337

Cited by 25 publications

(27 citation statements)

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“…A higher expression level of AtP7B is correlated with an unfavorable response to platinum drug treatment in ovarian, esophageal and oral squamous cell carcinoma (19,23,24). We recently reported that AtP7B mrnA and protein expression levels are associated with cDDP resistance in nsclc xenografts (14).…”

Section: Discussionmentioning

confidence: 99%

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ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer

Inoue

Matsumoto²,

Yamada³

et al. 2010

Oncology Letters

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Abstract. copper-transporting P-type adenosine triphosphatase (AtP7B) is reportedly associated with platinum drug resistance in various solid tumors. However, the impact of AtP7B on platinum drug resistance in non-small cell lung cancer (nsclc) remains unclear. We investigated in vitro cisplatin (cDDP) sensitivity using the collagen gel-droplet embedded culture drug sensitivity test. the AtP7B mrnA expression level in each specimen was also examined using real-time polymerase chain reaction. the relationship between AtP7B expression and in vitro cDDP sensitivity was then evaluated. the AtP7B mrnA expression levels in cDDPresistant tumors were significantly higher than those in the cDDP-sensitive group (p=0.015; Mann-Whitney U test). our results suggested that AtP7B expression is a promising chemoresistance marker for cisplatin. Introductionthe anticancer drug cisplatin (cDDP), which contains platinum, is widely used for the treatment of solid tumors such as testicular, ovarian, cervical, bladder, head and neck, as well as non-small cell lung cancer (nsclc) (1). cDDP has been a key drug in chemotherapy against nsclc for more than 20 years.However, the overall response rate to cisplatin as a single agent against nsclc is no more than 20% (2). Furthermore, the development of resistance to cDDP is common during treatment of nsclc patients, and is an important concern for clinical oncologists. thus, exploring chemoresistance markers is significant. Mechanisms of CDDP resistance include a decrease in drug accumulation and enhanced detoxification, but an increase in DNA repair efficiency. However, studies are mainly limited to in vitro or in vivo experiments and none of the examined markers have been validated as common contributors to clinical cDDP resistance or the prognosis of patients with nsclc (3).copper-transporting P-type adenosine triphosphatase (AtP7B) plays a key role in copper distribution inside cells. AtP7B is expressed in liver and kidney and, to a lesser extent, in the brain in normal individuals (4,5). AtP7B is responsible for the export of copper from the liver; thus, mutations that disable the function of AtP7B may lead to excessive hepatic copper accumulation, as suggested by the impairment of biliary copper excretion in patients with Wilson disease (6). Previous studies suggested that the copper export system functions as efflux transporters for platinum drugs. Moreover, the immunohistochemical expression of AtP7B has been shown to be associated with resistance to platinum drugs in certain solid tumors (3,(7)(8)(9). However, the expression of AtP7B and its impact on cDDP resistance in nsclc have yet to be thoroughly investigated.this study aimed to investigate the predictive value of AtP7B gene expression on in vitro chemosensitivity to cDDP, using surgically resected specimens from patients with nsclc. Materials and methodsStudy population. eligible patients included those with a histological diagnosis of nsclc. these patients had not received chemotherapy nor radiotherapy and had undergone surgic...

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Section: Discussionmentioning

confidence: 99%

“…Alterations in copper homeostasis can cause severe problems (18). For example, Wilson disease, an autosomal recessive disease of copper transport, is characterized by chronic liver and/or neurological disorders, occasionally accompanied by kidney damage (19,20).…”

Section: Discussionmentioning

confidence: 99%

ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer

Inoue

Matsumoto²,

Yamada³

et al. 2010

Oncology Letters

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“…These copper transporters have also been functionally implicated in resistance to several platinum compounds, including cisplatin, carboplatin and oxaliplatin (Samimi et al, 2004). Among the solid tumors, ATP7B is shown to be overexpressed in several tumor types including gastric, breast, esophageal, hepatocellular, colorectal, uterine, and oral squamous cell carcinomas (Higashimoto et al, 2003; Kanzaki et al, 2002; Miyashita et al, 2003; Nakayama et al, 2004; Ohbu et al, 2003; Sugeno et al, 2004). Primary function of ATP7A and ATP7B is to transport copper into the lumen of trans-Golgi network (TGN) to facilitate biosynthesis of copper-dependent enzymes.…”

Section: Strategies For Reversing Platinum Resistancementioning

confidence: 99%

Novel strategies for reversing platinum resistance

Shahzad

López-Berestein

Sood

2009

Drug Resistance Updates

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Platinum based drugs continue to be the mainstay of therapy for ovarian cancer. Along with adverse effects, chemoresistance (intrinsic or acquired) has become a major limitation in the management of recurrent disease. Even though much is known about the effects of platinum drugs on cancer cells, the mechanisms underlying resistance are poorly understood. In this review, we summarize the current data on chemoresistance and discuss novel strategies to reverse resistance to platinum-based drugs. The most important targets highlighted here include Aurora kinases, PARP, ATP7B, and ERCC1. Furthermore, we discuss the implications of these novel approaches for ovarian cancer treatment.

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“…The link between the Cu-ATPase ATP7B and cell response to DDP has been particularly well documented. ATP7B was found to be overexpressed in several solid tumors and in cultured cells; the increase in the ATP7B levels correlated with an increased resistance to DDP (18,(21)(22)(23)(24). In ovarian carcinoma cells, ATP7B was detected in vesicles resembling exosomes, prompting the suggestion that ATP7B facilitates DDP efflux (25).…”

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confidence: 99%

Functional Interactions of Cu-ATPase ATP7B with Cisplatin and the Role of ATP7B in the Resistance of Cells to the Drug

Leonhardt

Gebhardt

Mössner

et al. 2009

Journal of Biological Chemistry

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Cisplatin is a widely used chemotherapeutic agent for treatment of ovarian, testicular, lung, and stomach cancers. The initial response to the drug is robust; however, tumor cells commonly develop resistance to cisplatin, which complicates treatment. Recently, overexpression of the Cu-ATPase ATP7B in ovary cells was linked to the increased cellular resistance to cisplatin; and the role for Cu-ATPases in the export of cisplatin from cells was proposed. Our results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance. In hepatocytes, we observed no correlation between the levels of endogenous ATP7B and the resistance of cells to cisplatin. Unlike copper, cisplatin does not induce trafficking of ATP7B in hepatoma cells, neither does it compete with copper in a transport assay. However, cisplatin binds to ATP7B and stimulates catalytic phosphorylation with EC 50 similar to that of copper. Mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity. Thus, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug. The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin. Cisplatin, cis-diamminedichloroplatinum (DDP),3 is a common anti-tumor agent that is used to treat many types of cancer. It is especially prescribed for testicular, ovarian, bladder, liver, lung, and stomach cancers (1-5). DDP mediates its cytotoxic effects by binding to DNA, forming the intrastrand crosslinks and thus causing an inhibition of DNA synthesis and repair with eventual cell death (6, 7). The initial tumor response to the treatment with DDP is robust; however, the efficacy of treatment decreases with longer and repetitive therapy cycles. The resistance arises rapidly and is sufficient to cause a failure of DDP therapy (8). The mechanisms by which cells develop resistance to DDP are not fully understood. Detoxification of DDP, enhanced repair and tolerance of DNA adducts, inhibition of apoptosis, impaired uptake and increased efflux of the drug may contribute to the acquired resistance of cells (9 -13).Recently, an unexpected connection was discovered between the resistance of cells to DDP and cellular copper metabolism (14 -16). Either down-regulation of CTR1 (49), a transporter responsible for the uptake of copper, and/or up-regulation of the copper-transporting ATPases (Cu-ATPases) responsible for copper efflux were found to increase cells resistance to DDP, although correlation between the levels of CTR1 and resistance were not always observed (17). The DDP-resistant cells were shown to have a lower copper content (18), and...

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Expression of copper-transporting P-type adenosine triphosphatase in human esophageal carcinoma

Cited by 25 publications

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ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer

ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer

Novel strategies for reversing platinum resistance

Functional Interactions of Cu-ATPase ATP7B with Cisplatin and the Role of ATP7B in the Resistance of Cells to the Drug

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