The role of copper transporter ATP7A in platinum-resistance of esophageal squamous cell cancer (ESCC)

Li, Zhuanghua; Zheng, Rongjie; Chen, Jingtang; Jia, Jun; Qiu, Miao Zhen

doi:10.7150/jca.16117

Cited by 24 publications

(22 citation statements)

References 31 publications

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“…ATP7A serves an important role in Pt resistance by transporting Pt drugs out of cells ( 30 ). The overexpression of ATP7A was associated with Pt resistance in oesophageal squamous cell cancer ( 31 ), NSCLC ( 32 ), CRC ( 33 ) and ovarian cancer ( 34 ). Overexpressed ATP7A was also identified to predict a poor prognosis in patients with NSCLC receiving Pt-based chemotherapy ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels

et al. 2018

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Resistance to oxaliplatin (L-OHP) is a major obstacle to successful chemotherapy in colorectal cancer (CRC). In the present study, the ability of gambogic acid (GA) to reverse L-OHP resistance in CRC LoVo cells was investigated. L-OHP-resistant LoVo/L-OHP cells were established by exposing them to increasing concentrations of L-OHP. GA-reversed L-OHP-sensitive LoVo/L-OHP/GA cells were established by exposure to 0.5 µmol/l GA for 2 weeks. A Cell Counting Kit-8 assay was used to assess levels of proliferation. Flow cytometry was applied to detect apoptosis rates. Transwell assays were used to analyse invasion. Inductively coupled plasma mass spectrometry was used to determine intracellular platinum (Pt) content. Western blot analysis was used to reveal the protein levels of Human copper transporter 1 (hCTR1), Copper-transporting p-type adenosine triphosphatases 1 (ATP7A) and Copper-transporting p-type adenosine triphosphatases 2 (ATP7B). LoVo/L-OHP and LoVo/L-OHP/GA cell lines were successfully established, and it was identified that L-OHP inhibited the proliferation of LoVo, LoVo/L-OHP and LoVo/L-OHP/GA cells in a dose-dependent manner. Compared with the parent LoVo cells, the anti-apoptosis and invasion properties of LoVo/L-OHP cells were enhanced, and were reversed by GA treatment. Intracellular Pt content was highest in the LoVo cells, followed by LoVo/L-OHP/GA cells, and then lowest in the LoVo/L-OHP cells. Downregulated hCTP1 and upregulated ATP7A and ATP7B were associated with L-OHP resistance, and GA reversed the resistance by increasing levels of hCTR1 and decreasing levels of ATP7A and ATP7B. In conclusion, GA has the potential ability to reverse L-OHP resistance in CRC cells by increasing intracellular Pt content, which it achieves by increasing hCTR1 levels and decreasing ATP7A and ATP7B levels. GA may represent a promising treatment agent for L-OHP resistance.

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Section: Discussionmentioning

confidence: 99%

Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels

et al. 2018

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“…As summarized in Table , both in vivo and in vitro models indicate that ATP7A is correlated with platinum drug resistance in different tumor types. In vitro studies, ATP7A levels in platinum‐resistant cells are much higher than that in platinum‐sensitive cells . Moreover, ATP7A knockdown by siRNA partially reverses resistance to platinum drugs .…”

Section: Atp7a/7b and Platinum Drug Resistancementioning

confidence: 99%

“…In vitro studies, ATP7A levels in platinum-resistant cells are much higher than that in platinum-sensitive cells (18)(19)(20). Moreover, ATP7A knockdown by siRNA partially reverses resistance to platinum drugs (19)(20)(21). In addition to cisplatin, carboplatin and oxaliplatin, ATP7A confers resistance to multiple anticancer agents, including vincristine, paclitaxel, SN-38, etoposide, doxorubicin, and mitoxantron (22)(23)(24).…”

Section: Atp7a/7b and Platinum Drug Resistancementioning

confidence: 99%

Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy

Yin

Liu

et al. 2018

IUBMB Life

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Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression. We also discuss the possible mechanisms of platinum drug resistance mediated by ATP7A/7B and provide novel strategies for overcoming resistance. This review may be helpful for understanding the roles of ATP7A and ATP7B in platinum drug resistance. © 2018 IUBMB Life, 70(3):183-191, 2018.

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“…Recent studies have revealed that copper and platinum drug may share the same transporter system 5 . Copper transporters not only maintain copper homeostasis, but also are involved in the transport of platinum drug and ultimately contribute to platinum resistance 6 - 8 . ATP7B, a copper efflux transporter, has been demonstrated to deliver platinum drug out of cells.…”

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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The role of copper transporter ATP7A in platinum-resistance of esophageal squamous cell cancer (ESCC)

Cited by 24 publications

References 31 publications

Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels

Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels

Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy

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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