Connecting copper and cancer: from transition metal signalling to metalloplasia

Abstract

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.

Fig. 1 |. Overview of systemic and cellular copper homeostasis.

Human copper homeostasis involves a number of key molecular targets. Ceruloplasmin (CP) is the major protein carrier for exchangeable copper in blood plasma for circulation and delivery to organ and tissue systems. At the cellular level, the STEAP family of metalloreductases and copper ion channel copper transporter 1 (CTR1) enable high-affinity copper uptake, with a diverse array of cytoplasmic and mitochondrial metallochaperones (antioxidant protein 1 (ATOX1), copper chaperone for superoxide dismutase (CCS), synthesis of cytochrome oxidase 1 (SCO1), SCO2, copper chaperone for cytochrome c oxidase 11 (COX11), COX17, ATPase 7A (ATP7A) and ATP7B) working in concert to ensure targeted insertion of copper into metalloprotein. The ATP-driven transmembrane copper ion pumps ATP7A and ATP7B perform both copper export and metallochaperone functions. The thiol-rich proteins metallothionein 1 (MT1) and MT2 bind multiple copper ions and can serve as a copper storage reservoir. In addition, the abundant peptide and antioxidant glutathione (GSH) can also participate directly or indirectly in regulating cellular copper pools. Within the mitochondria, cytochrome c oxidase assembly factor 6 (COA6) and SCO2 help maintain the redox balance of SCO1 and in turn its copper binding and delivery to cytochrome c oxidase (COX). Together, these proteins maintain appropriate intracellular copper bioavailability and ensure metallation of copper-dependent enzymes, including COX, superoxide dismutase 1 (SOD1) and oxygenase/oxidase enzymes, including tyrosinase, lysyl oxidase (LOX), dopamine β-hydroxylase (DBH) and copper amine oxidases. Aberrant elevations in copper levels have been reported in tumours or serum of animal models and patients with various cancers, including breast, lung, gastrointestinal, oral, thyroid, gall bladder, gynaecologic and prostate cancers.

Fig. 2 |. Copper metalloallostery and signalling promotes cell growth/proliferation and autophagy pathways.

Besides the traditional role of copper as a static cofactor for protein function, emerging evidence shows that copper is able to serve as both a negative allosteric regulator and a positive allosteric regulator of enzyme activity to influence foundational cellular pathways. As an example of negative metalloallostery, copper binds and inhibits phosphodiesterase 3B (PDE3B) to inhibit cyclic AMP (cAMP) degradation (part a) and promote cAMP-dependent lipolysis (part c), the breakdown of triglycerides into fatty acids and glycerol that is essential for fat metabolism. In the context of positive metalloallostery, copper acts on mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 and enhances their ability to phosphorylate extracellular signal-regulated kinase 1 (ERK1) and ERK2) (part b), stimulating RAF–MEK–ERK signalling (part c). Unc51-like kinase 1 (ULK1) and ULK2 provide a second example of copper-dependent kinase regulation, with copper able to relieve ULK1 and ULK2 inhibition and increase kinase activity in response to amino acid starvation (parts b,c). Finally, recent work has identified a role for copper signalling in promotion of protein degradation by positive allosteric activation of the E2 conjugating enzyme clade UBE2D1–UBE2D4 (part c). Therefore, copper-dependent kinase signalling can regulate cell growth/proliferation through MEK1 and MEK2 and autophagy through ULK1and ULK2 (part c). mTOR, mechanistic target of rapamycin.

Fig. 3 |. Therapeutic strategies to target cuproplasia in cancer.

Copper status can be leveraged as a cancer vulnerability, where the two major current treatment approaches targeting this nutrient include Cu(I) chelators to deplete copper pools that drive tumour proliferation and metastasis pathways (part a) or copper ionophores to supplement copper and drive cuproptosis, an oxidative stress-inducing form of cell death triggered by excess copper (part b). a | Copper chelators such as tetrathiomolybdate (TTM) can be used in combination therapy to augment the efficacy of kinase inhibitor drugs for oncogenic signalling pathways, particularly BRAF-driven MAPK signalling. b | Copper ionophores such as disulfiram (DSF) or elesclomol (ES) can be used to induce cuproptosis by inducing oxidative stress by overwhelming native antioxidant systems such as in mitochondria. c | TTM can also be used to deplete copper in the primary tumour and/or the metastatic niche to impede copper-dependent tumour metastasis without impairing the function of healthy tissue, as shown by long-term clinical trials in patients with triple-negative breast cancer. This chelator targets a key antioxidant protein 1 (ATOX1)–ATPase 7A (ATP7A)–lysyl oxidase (LOX) copper nexus that drives invasion and metastasis by impacting collagen deposition and structure and decreases the number of VEGFR2⁺ endothelial progenitor cells in circulation that prime the metastatic niche. MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin.