Copper Transport Systems in Platinum-Based Chemotherapy

The efficacy of platinum-based chemotherapeutic agents such as cisplatin and carboplatin is intimately linked to the cellular machinery that governs copper homeostasis. Uptake of platinum drugs is largely mediated by the high-affinity copper transporter hCtr1, which ordinarily imports Cu(I) but also facilitates entry of platinum complexes. Once inside the cell, copper chaperones such as ATOX1 shuttle metal ions to P-type ATPases, notably ATP7A and ATP7B, which reside in the trans-Golgi network under basal conditions. In response to elevated copper or platinum burdens, ATP7A and ATP7B relocate to vesicular membranes, promoting sequestration and efflux of excess metal. This dynamic trafficking not only maintains copper balance but also serves as a key mechanism of platinum-drug detoxification, contributing to acquired chemoresistance. Modulation of transporter expression, post-translational regulation and interactions with small-molecule chelators all influence drug retention and tumour cell survival. A detailed mechanistic understanding of these pathways has opened avenues for sensitising resistant tumours through pharmacological intervention in copper transport systems.

Research from Nature Portfolio

Recent studies have elucidated how the copper chelator tetrathiomolybdate (TM) directly targets the metal-binding domains of the copper-efflux ATPase ATP7B. Structural analyses reveal that TM induces dimerisation of the ATP7B metal-binding domain via a unique Mo₂S₆O₂ cluster, effectively displacing copper and preventing platination of the protein. This Mo-bridging mechanism not only impairs ATP7B trafficking but also diminishes its capacity to export cisplatin, thereby restoring drug accumulation within resistant cells. Complementary biochemical investigations demonstrate that TM can bridge multiple domains within the same ATPase, forming intramolecular crosslinks that stabilise an inactive conformation. These insights provide a molecular basis for repurposing TM as an adjuvant to overcome copper-mediated platinum resistance.

Copper Transport Systems in Platinum-Based Chemotherapy publication trend

The graph below shows the total number of articles in copper transport systems in platinum-based chemotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

hCtr1: High-affinity copper transporter 1, a membrane protein that imports Cu(I) and platinum-based drugs into cells.

ATOX1: A cytosolic copper chaperone that delivers Cu(I) to ATP7A and ATP7B within the secretory pathway.

ATP7A and ATP7B: Copper-transporting P-type ATPases responsible for exporting excess copper and sequestering platinum drugs in vesicles.

Tetrathiomolybdate (TM): A copper chelator that binds to metal-binding domains of copper ATPases, inhibiting their ability to export platinum.

Cisplatin: A platinum-based chemotherapeutic agent that forms DNA crosslinks to induce tumour cell apoptosis.

References

1. Distinct Mechanisms for Ctr1-mediated Copper and Cisplatin Transport*. Journal of Biological Chemistry (2007).
2. Determinants for Simultaneous Binding of Copper and Platinum to Human Chaperone Atox1: Hitchhiking not Hijacking. PLOS ONE (2013).
3. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells. BMC Cancer (2008).
4. Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs. Cells (2019).
5. Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein. Nature Communications (2019).
6. Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis. International Journal of Molecular Sciences (2018).