Abstract
BackgroundCopper export protein ATP7A is important for maintaining copper homeostasis. Recent studies have shown that copper transporters are also involved in the transport of platinum. The goal of this study was to determine the role of ATP7A in the platinum-resistance of non-small cell lung cancer (NSCLC).MethodsSensitivities to platinums were detected by MTT assay and drug-resistance related genes were analyzed by real-time PCR and immunoblotting between DDP-sensitive A549 and the corresponding DDP-resistant cell subline (A549/DDP). ATP7A expression was evaluated by immunohistochemistry in tumor tissues of unresectable NSCLC patients who received cisplatin-basing chemotherapy.ResultsThe expression of ATP7A was significantly higher in A549/DDP cell subline than in A549 cells at both mRNA and protein levels. The silencing of ATP7A expression in A549/DDP by siRNA partially reversed DDP-resistance (29.62%) and increased cell apoptosis. ATP7A expression was detected in 41.6%of NSCLC patients, but not in adjacent stroma nor normal lung tissues. ATP7A-positive patients had a significantly poorer histological grade (p = 0.039) and poorer response to platinum-basing chemotherapy (p = 0.001) compared with ATP7A-negative patients. Cox's proportional hazards analysis showed that ATP7A expression was an independent prognostic factor for overall survival (p = 0.045).ConclusionsATP7A overexpression played an important role in platinum-resistance of NSCLC, and was a negative prognostic factor of NSCLC patients treated with platinum-based chemotherapy.
Highlights
Copper export protein Adenosine triphosphatase (ATP7A) is important for maintaining copper homeostasis
Evidences suggested that some copper influx transporters especially CTR1 were involved in the cellular uptake of DDP, CBDCA and L-OHP, and the other two copper transporters ATP7A and ATP7B import copper to golgi apparatus which regulates the efflux of DDP [6]
ATP7A was overexpressed in A549/DDP The expression of ATP-binding cassette (ABC) transporters in A549 and A549/DDP cell lines were examed by real-time PCR and immunoblotting
Summary
Copper export protein ATP7A is important for maintaining copper homeostasis. Recent studies have shown that copper transporters are involved in the transport of platinum. The goal of this study was to determine the role of ATP7A in the platinum-resistance of non-small cell lung cancer (NSCLC). There are a viariety of factors contributing to platinum-resistance, including decreased drug accumulation, Copper uptake protein CTR1, copper export proteins ATP7A and ATP7B are important for maintaining copper homeostasis. Evidences suggested that some copper influx transporters especially CTR1 were involved in the cellular uptake of DDP, CBDCA and L-OHP, and the other two copper transporters ATP7A and ATP7B import copper to golgi apparatus which regulates the efflux of DDP [6]. ATP7B has been reported to relate to DDP-resistance first [8,9] Another copper transporter ATP7A has been implicated in platinumresistance later [10,11]
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