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

Abstract

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.

Current Biomedical Use of Copper Chelation Therapy

“…Patients not responding to platinum-based chemotherapy have increased serum copper content up to 160% compared to responding patients [132], suggesting a link between maintenance of copper homeostasis and drug resistance. Copper transport proteins play a role in cisplatin, the most used platinum based chemotherapeutic drug [133,134]. Cellular copper homeostasis is accurately regulated by the CTR1, responsible for specific copper cellular uptake into cells, and the copper-transporting P-type ATPases (ATP7A and ATP7B), which are mainly responsible for supplying copper to cuproenzymes and for the removal of excess copper out of the cell.…”

“…As a matter of fact, CTR1 can also transport platinum drugs into the cell and its expression has been associated with cisplatin sensitivity [135]. Conversely, ATP7A and ATP7B may promote cisplatin cellular efflux, reducing drug cellular accumulation and leading to reduced efficacy; accordingly, increased expression of ATP7A and ATP7B correlates with platinum drug resistance [133]. Importantly, expression and activity of CTR1, ATP7A and ATP7B are modulated by intracellular Cu levels.…”

Label-Free Bioelectrochemical Methods for Evaluation of Anticancer Drug Effects at a Molecular Level

“…It was suggested that translocation of platinum drugs by ATP7A and ATP7B and sequestration of these drugs in the ATPase amino-terminal extension are Development of cell resistance to cisplatin-based therapies represents a critical issue that considerably reduces the efficacy of platinum anticancer drugs. Interaction of cisplatin with mammalian Cu + -ATPases, ATP7A and ATP7B, also known as Menkes and Wilson disease proteins, has been associated with resistance of cancer cells to platinum drugs [55][56][57]. ATP7A and ATP7B, which are localized in the trans-Golgi network (TNG), perform active transfer of copper across the membrane into the TGN lumen by ATP utilization and are responsible for regulating intracellular copper levels [58].…”

A Preliminary Study of Cu Exposure Effects upon Alzheimer’s Amyloid Pathology

“…β-actin was used as a control, and two copper-transporting ATPases, ATP7B and ATP7A were also used as comparisons. The two transporters are notably copper-efflux transporters, and their expression is regulated by copper levels [79]. The results of the SDS-PAGE are depicted in Figure 4.…”