Abstract 246: Role for ATP7A copper transporter in cisplatin resistance, tumorigenesis and metastasis

Copper is a trace metal with a ready capacity to gain or donate electrons. This property is harnessed by numerous enzymes to perform vital functions in the body. In humans, copper is required for various biochemical processes including cellular respiration, connective tissue development, iron transport, and pigmentation. The same redox property which makes copper useful can also have deleterious effects if the proper balance is not maintained. Hence a delicate balance of copper should be maintained in the body. Cellular copper homeostasis is maintained by several different proteins. Ctr1 (copper transporter 1) has high affinity for copper and aids in copper uptake into the cell. ATP7A and ATP7B are copper exporting ATPases, which share 60% identity, are functionally homologous. Under low intracellular copper concentrations, ATP7A is localized to the TGN (trans-Golgi network), where it transports copper to newly synthesized cuproenzymes. Under elevated copper concentrations, ATP7A traffics to post TGN vesicles and to the plasma membrane, subsequently releasing the copper load by fusion with the plasma membrane. There are emerging studies implicating a role of ATP7A in resistance against the platinum-based chemotherapy agent, cisplatin, which is widely used to treat cancer. Previous studies have correlated ATP7A expression to the sensitivity of cultured cells to cisplatin. Here, we report that deletion of the Atp7a gene in isogenic RAS-transformed mouse embryonic fibroblast (MEF) cells not only confers sensitivity to cisplatin, but markedly prevents tumor formation in the absence of chemotherapy agent. Deletion of Atp7a in the breast cancer cell line, 4T1, was also found to suppress tumorigenesis and markedly reduce metastasis to the lungs. The ATP7A knockout 4T1 cells showed a significant decrease in Lysyl Oxidase (LOX) activity as compared to the 4T1WT cells. Given the numerous studies showing that LOX family involved in breast tumor metastasis, ATP7A might play a role in tumor progression by virtue of its requirement for metallating LOX. The ATP7A knockout 4T1 cells exhibited reduced survival as compared to the 4T1WT cells in the presence of physiological concentrations of hydrogen peroxide or hypoxia, suggesting that hyper-accumulation of copper sensitizes these cells to ROS production. Taken together, these findings identify the ATP7A copper transporter at the nexus of platinum-drug resistance, tumorigenesis and metastatic pathways, underscoring its potential as a therapeutic drug target at multiple stages of carcinogenesis. Citation Format: Vinit Shanbhag, Nikita Gudekar. Role for ATP7A copper transporter in cisplatin resistance, tumorigenesis and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 246.