Elucidating the roles of the ATP7A copper transporter in cultured cells, tumor growth and metastasis

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Copper is an essential trace metal in all organisms. In humans, copper plays structural and catalytic roles for numerous enzymes and is required for cellular respiration, connective tissue development, pigment formation, iron absorption and mobilization, integrity of the central nervous and immune systems. However, copper can also be toxic when present in excessive amounts, owing to its ability to facilitate reactive oxygen species (ROS) production. Because of the vital yet potentially toxic roles of copper, organisms have evolved delicate homeostatic control of copper uptake, intracellular distribution and export. Cellular copper homeostasis is maintained by several key regulators including: Copper transporter 1 (CTR1) and copper efflux transporters (ATP7A and ATP7B). Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, leading to Menkes disease (systemic copper deficiency) or Wilson disease (copper overload). ATP7A controls the cellular export of copper and the function of ATP7A is largely regulated by its subcellular localization. To regulate copper homeostasis, ATP7A cycles between the trans-Golgi network (TGN) and the plasma membrane constitutively or in a copper-dependent manner. A single endocytic di-leucine motif in the cytoplasmic tail of ATP7A was previously shown to regulate ATP7A internalization. Other than the maintenance of copper homeostasis, there are emerging studies demonstrating critical roles of ATP7A in cancer drug resistance and cancer progression. The platinum-based chemotherapy drug cisplatin is widely used to treat cancer. However, clinical use of cisplatin is limited by either severe side effects or acquired resistance. Copper transport pathways are proposed to be responsible in part for tumor resistance to cisplatin. In vitro observations suggested that high levels of ATP7A mediate vesicular sequestration of cisplatin and contribute to drug resistance. Furthermore, increased ATP7A expression is associated with clinical resistance to cisplatin chemotherapy and poor progno