Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

Tian, Yang; Chen, Mingwei; Chen, Tianjun; Thakur, Asmitananda

doi:10.3892/ol.2015.3531

Cited by 31 publications

(19 citation statements)

References 32 publications

(32 reference statements)

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“…Cellular adaptations that lead to this condition promote many cancer types to become more aggressive with a higher tendency to metastasize, leading to significantly worse prognosis. [18][19][20] This principle is consistent with our findings, as higher dose pairings that moved above the IC50 of each respective drug, the result was antagonism (CI > 1), supporting the buffering antagonism phenomenon. At the very lowest dose-pairings, antagonism was also observed for all four cell lines.…”

Section: Quantification Of the Percentage Of Cells In Each Phase Of Tsupporting

confidence: 90%

Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy

Inkol

Poon

Mutsaers

2020

Vet Comparative Oncology

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Osteosarcoma (OSA) is the most common primary bone cancer in children, adolescents and dogs. Current combination surgical and chemotherapeutic treatments have increased survival. However, in recurrent or metastatic disease settings, the prognosis significantly decreases, representing an urgent need for better second-line and novel chemotherapeutics. The current gold standard for combination chemotherapy in OSA often includes a platinum agent, for example, cisplatin or carboplatin. These platinum agents are shuttled within the cell via copper transporters. Recent interest in targeting copper transport has been directed towards antioxidant protein 1 (Atox1) and copper chaperone for superoxide dismutase 1 (CCS), with Atox1 demonstrating the ability to aggregate platinum agents, preventing them from forming DNA adducts. DC_AC50 is a small molecule inhibitor of both Atox1 and CCS. To assess the impact of targeting these pathways on chemotherapy response, two human and two canine OSA cell lines were utilized. After treatment with single agent or combination drugs, cell viability was evaluated and pharmacological synergism calculated using the combination index method. Apoptosis, cell cycle distribution, clonogenic survival and migration were also evaluated. DC_AC50 synergised with carboplatin in combination treatment of human and canine OSA cells to reduce cancer cell viability. DC_AC50-treated cells were significantly less mitotically active, as demonstrated by decreased expression of phospho-histone H3 and cell cycle analysis. DC_AC50 also potentiated carboplatin-induced apoptosis in OSA cells and decreased clonogenic survival. Finally, DC_AC50 reduced the migratory ability of OSA cells. These results justify further investigation into inhibiting intracellular copper chaperones as a means of reducing/preventing acquired chemotherapy resistance.

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Section: Quantification Of the Percentage Of Cells In Each Phase Of Tsupporting

confidence: 90%

Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy

Inkol

Poon

Mutsaers

2020

Vet Comparative Oncology

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“…(Chen et al 2016 ). In fact, in some cancers ATP7B expression has been connected to tumor-cell differentiation and alteration of outcome for platinum-based chemotherapy drugs (Dmitriev 2011 ; Kuo et al 2007 ; Li et al 2014 ; Martinez-Balibrea et al 2009 ; Yang et al 2015 ). For instance, cisplatin, a potent anti-cancer agent used against solid tumors of various cancers has been shown to bind to both Atox1 and ATP7B, perhaps processes governing cell resistance against this drug (Dmitriev 2011 ; Palm-Espling et al 2013 ; Palm et al 2011 ).…”

Section: Discussionmentioning

confidence: 99%

The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations

Ariöz

Wittung-Stafshede

2017

Biometals

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Wilson Disease (WD) is a hereditary genetic disorder, which coincides with a dysfunctional copper (Cu) metabolism caused by mutations in ATP7B, a membrane-bound P 1B -type ATPase responsible for Cu export from hepatic cells. The N-terminal part (* 600 residues) of the multi-domain 1400-residue ATP7B constitutes six metal binding domains (MBDs), each of which can bind a copper ion, interact with other ATP7B domains as well as with different proteins. Although the ATP7B's MBDs have been investigated in vitro and in vivo intensively, it remains unclear how these domains modulate overall structure, dynamics, stability and function of ATP7B. The presence of six MBDs is unique to mammalian ATP7B homologs, and many WD causing missense mutations are found in these domains. Here, we have summarized previously reported in vitro biophysical data on the MBDs of ATP7B and WD point mutations located in these domains. Besides the demonstration of where the research field stands today, this review showcasts the need for further biophysical investigation about the roles of MBDs in ATP7B function. Molecular mechanisms of ATP7B are important not only in the development of new WD treatment but also for other aspects of human physiology where Cu transport plays a role.

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“…Moreover, the expression of ATP7B is associated with the response to platinum-based chemotherapy in patients with ovarian cancer or several other cancers 9 - 14 . Currently, only a limited number of studies have focused on the role of ATP7B in platinum resistance in NSCLC patients, resulting in highly conflicting results 15 - 17 . This indicates the need for further studies to clarify the clinical significance of ATP7B in NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

Gene expression and single nucleotide polymorphism of ATP7B are associated with platinum-based chemotherapy response in non-small cell lung cancer patients

Li¹,

Chen²,

Yin³

et al. 2018

J. Cancer

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Objectives: Platinum-based chemotherapy is first-line treatment for non-small cell lung cancer (NSCLC) patients. The efficacy is limited by drug resistance. Recent studies suggest that ATP7B, a copper efflux transporter, may be involved in platinum resistance. However, the clinical significance of ATP7B expression in NSCLC is controversial. Moreover, the effects of single nucleotide polymorphisms (SNPs) in ATP7B gene on the response to platinum-based chemotherapy are scarcely understood. The aim of our study is to evaluate the clinical value of ATP7B in NSCLC patients and explore the interrelationships between ATP7B SNPs and protein expression, and their association with chemotherapy response.Materials and Methods: A total of 247 NSCLC patients were recruited in this study. Among them, 158 patients who received platinum-based chemotherapy were used to explore the interrelationships between ATP7B SNPs, protein expression and chemotherapy response, while 89 patients who underwent surgical resection were used to further investigate the association between ATP7B SNPs and expression level. We genotyped 15 SNPs of ATP7B by Sequenom MassARRAY and determined ATP7B protein levels by immunohistochemistry.Results: Patients with ATP7B-negative tumors had improved chemotherapeutic response (p=0.025) and better overall survival (p=0.044) compared with the patients with ATP7B-positive tumors. The multivariate Cox regression analysis revealed that ATP7B expression was an independent prognostic factor (HR=0.639, 95%CI=0.424-0.962, p=0.032). Moreover, we found that the rs9526814 GG genotype was significantly associated with favorable response to platinum-based chemotherapy when compared with TT+TG genotypes (OR=0.362, 95CI%=0.140-0.935, p=0.036). Mechanistically, rs9526814 GG genotype showed a strong trend towards reduced expression level of ATP7B compared with the TT+TG genotypes (p= 0.048).Conclusion: Our findings indicate that ATP7B rs9526814 may contribute to platinum resistance by influencing ATP7B gene expression and can be used as a potential biomarker to predict the sensitivity of platinum-based chemotherapy in NSCLC patients.

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Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

Cited by 31 publications

References 32 publications

Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy

Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy

The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations

Gene expression and single nucleotide polymorphism of ATP7B are associated with platinum-based chemotherapy response in non-small cell lung cancer patients

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