Copper Metabolism and Cell Death Mechanisms in Cancer

Copper is an essential trace element that underpins key biochemical processes, including mitochondrial respiration, antioxidant defence and connective tissue synthesis. Cellular copper levels are tightly regulated by specialised transporters, chaperones and exporters to balance its vital roles against potential toxicity. In cancer, dysregulated copper uptake and retention support tumour proliferation, angiogenesis and metastasis. Recent discoveries have defined cuproptosis, a copper-dependent form of regulated cell death triggered by direct binding of copper to lipoylated tricarboxylic acid cycle enzymes, resulting in proteotoxic stress. Alongside cuproptosis, copper overload or depletion can engage ferroptosis, apoptosis and autophagy pathways via reactive oxygen species and alterations in mitochondrial function. Therapeutic strategies now aim to exploit these vulnerabilities through copper chelators, ionophores and copper-based complexes to selectively induce tumour cell death or impair metastatic potential.

Research from Nature Portfolio

A novel strategy to rebalance cellular copper pools in inflammatory and tumour-associated cells has revealed that targeting mitochondrial copper(II) with a dimeric metformin derivative reduces the NAD(H) pool, remodels metabolic and epigenetic programmes and reverses cell plasticity. This approach demonstrates the potential to impair pro-tumorigenic phenotypes by depriving cells of copper’s redox activity. In triple-negative breast cancer, selective copper depletion using an oral chelating agent uncovers a subpopulation of SOX2/OCT4-positive cells with elevated mitochondrial copper levels. Loss of copper from cytochrome c oxidase leads to energy stress via AMPK activation, reduced mTORC1 signalling and suppressed invasion, suggesting that copper chelation can specifically target cells with high metastatic capacity.

Copper Metabolism and Cell Death Mechanisms in Cancer publication trend

The graph below shows the total number of articles in copper metabolism and cell death mechanisms in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Cuproptosis: A novel form of regulated cell death initiated by copper binding to lipoylated mitochondrial enzymes, causing proteotoxic stress.

Ferroptosis: Iron-dependent cell death driven by lipid peroxidation and reactive oxygen species accumulation.

Copper chaperone: A protein that binds and delivers copper ions to specific cellular targets, preventing free-ion toxicity.

Chelator: A molecule that binds copper tightly, reducing its bioavailability and disrupting copper-dependent processes.

Ionophore: A compound that transports copper ions across cellular membranes, increasing intracellular copper levels.

References

1. New Roles for Copper Metabolism in Cell Proliferation, Signaling, and Disease*. Journal of Biological Chemistry (2008).
2. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers (2020).
3. Copper homeostasis and cuproptosis in health and disease. Signal Transduction and Targeted Therapy (2022).
4. A druggable copper-signalling pathway that drives inflammation. Nature (2023).
5. Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nature Communications (2021).
6. Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Molecular Oncology (2021).