The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy

Abstract

In the human body, copper (Cu) is a major and essential player in a large number of cellular mechanisms and signaling pathways. The involvement of Cu in oxidation-reduction reactions requires close regulation of copper metabolism in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concentrations of intratumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness or may even confer resistance to treatments. Once characterized, the dysregulated Cu metabolism is pinpointing several promising biomarkers for clinical use with prognostic or predictive capabilities. The altered Cu metabolism in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete, or increase Cu levels in tumors. The metallic nature of Cu as a chemical element is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclinical setting, and others are already in the clinic.

Keywords: cancer; copper homeostasis; diagnostic; prognostic; therapy.

Figure 1

Cellular copper homeostasis in hepatocytes (A) and fibroblasts (B). In cells, the internalization of reduced Cu occurs via Ctr1. Then, Cu is involved in the control of oxidative stress (red arrows) through a copper chaperone for superoxide dismutase protein (CCS) and cytoplasmic Cu/Zn superoxide dismutase 1 (SOD1). Copper can be stored in its main storage reservoir, the mitochondria, where the proteins COX17, Sco1, and Sco2 play a role in its incorporation into complex IV of the respiratory chain (green arrows). Nevertheless, in the mitochondrial pathway, the identity of the chaperone that carries Cu across the mitochondrial membranes is not clearly identified. The excess Cu can also be sequestered by metallothioneins (MT) and/or bound by glutathione (GSH; dashed purple arrows). (A) In hepatocytes, copper can be secreted via the bile duct or released in the blood stream bound to ceruloplasmin (Cp) after transport by Atox1 and ATP7B proteins (blue arrows) and transit in the trans-Golgi network (TGN). Cu is released into the blood stream and travels by binding to Cp, amino acids (AA), or albumin. (B) In fibroblasts, ATP7A carries Cu from Atox1 to the TGN for its integration into lysyl oxidase (LOX) or extracellular superoxide dismutase 3 (SOD3) before their extracellular release. In addition, the excess intracellular Cu can be removed from the cell through ATP7A and ATP7B.