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 intra-tumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness, or 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, while others are already in the clinic.

Cuproptosis-related genes signature is associated with tumor progression, PD-L1 stability and bystander T cells in esophageal carcinoma

“…Consistent with our reports, Cu concentration was also found to increase in tumor areas and even correlated with the grade of cancer [34][35][36]. High serum Cu levels were also found in cancer patients resistant to chemotherapy compared to patients responding to treatment [36] and promote the scatter and formation of secondary tumors by activating cell proliferation-related enzymes [23].…”

“…Previous studies suggested aberrant copper homeostasis (ACH) was highly associated with cancers such as bladder cancer, breast cancer, colorectal cancer, and prostate cancers [19][20][21][22]. Supporting this, in carcinogenesis, ACH was observed to contribute to the proangiogenic response via various molecular pathways, which played a fundamental role in cancer proliferation or angiogenesis [23]. Moreover, copper accumulation in cancer cells was also reported [24,25].…”

Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools

“…5 ). Many cancer types are associated with aberrantly elevated levels of copper in patient serum ( 4 , 80 ), where this metal nutrient regulates several proteins involved in tumor growth and proliferation ( 4 , 81 ). Our findings show that changes in copper oxidation state are also important to consider in these pathways.…”

Downregulated Copper Homeostasis-Related Gene FOXO1 as a Novel Indicator for the Prognosis and Immune Response of Breast Cancer

“…Cu metabolism needs to be strictly controlled to prevent various diseases, including metabolic syndrome [21]. Absolutely, disordered Cu homeostasis can lead to a wide variety of cancers, including BRCA, colorectal cancer, and prostate cancer [22]. Several studies suggested that Cu was equipped to activate the mitogen-activated protein kinase (MAPK) pathway and facilitated tumorigenesis and cancer growth [23].…”