Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes.
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 Cu(I)-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.
CAS High Magnetic Field Laboratory, CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry & Collaborative Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, Anhui, China. liuyz@ustc.edu.cn.
Zhaoyong
Z
Xi
Wei
W
Guo
Changlin
C
Tian
Fuyi
F
Wang
Yangzhong
Y
Liu
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D006801:Humans; D056511:Metallochaperones / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*
C474500:ATOX1 protein, human; D000970:Antineoplastic Agents; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D009944:Organoplatinum Compounds; D013844:Thiazoles; C504858:trans-(PtCl2(NH3)(thiazole)); D003300:Copper