Issue 3, 2014

Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes

Abstract

The transport system of platinum-based anticancer agents is crucial for drug sensitivity. Increasing evidence indicates that the copper transport system is also involved in the cellular influx and efflux of platinum drugs. The copper chaperone Atox1 has been shown to bind to cisplatin in vitro and in cells. Previous results reveal that copper binding promotes the reaction between Atox1 and cisplatin. Here, we have performed detailed solution NMR and ESI-MS experiments to investigate the effect of Cu(I) binding on the reactions of Atox1 with two antitumor active trans-platinum agents, trans-EE and trans-PtTz. Results indicate that, similar to the reaction of cisplatin, copper coordination also enhances the platination of Atox1 by two trans-platinum complexes, and platinum binds to the copper coordinating residues. However, copper binding promotes the trans-platinum transfer from Atox1 to dithiothreitol (DTT). This result is in contrast to the reaction of Atox1 with cisplatin, in which the presence of copper largely suppresses the platination of DTT. Additionally, both apo- and CuI-Atox1 react faster with trans-platinum complexes than with cisplatin, however, less protein aggregation is observed in the reaction of trans-platinum complexes. These results indicate that the roles of Atox1 in the regulation of cellular trafficking of platinum drugs are dependent on the coordination configurations.

Graphical abstract: Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes

Supplementary files

Article information

Article type
Paper
Submitted
15 Nov 2013
Accepted
06 Jan 2014
First published
07 Jan 2014

Metallomics, 2014,6, 491-497

Author version available

Spotlight

Advertisements