Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A.
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Research Article|
July 26 2013
Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification
Nataliya V. Dolgova;
Nataliya V. Dolgova
1
*Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E5
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Sergiy Nokhrin;
Sergiy Nokhrin
1
*Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E5
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Corey H. Yu;
Corey H. Yu
1
*Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E5
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Graham N. George;
Graham N. George
†Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E5
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Oleg Y. Dmitriev
Oleg Y. Dmitriev
2
*Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E5
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 30 2012
Revision Received:
June 10 2013
Accepted:
June 11 2013
Accepted Manuscript online:
June 11 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 454 (1): 147–156.
Article history
Received:
October 30 2012
Revision Received:
June 10 2013
Accepted:
June 11 2013
Accepted Manuscript online:
June 11 2013
Citation
Nataliya V. Dolgova, Sergiy Nokhrin, Corey H. Yu, Graham N. George, Oleg Y. Dmitriev; Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification. Biochem J 15 August 2013; 454 (1): 147–156. doi: https://doi.org/10.1042/BJ20121656
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