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research article

Bioavailable copper modulates oxidative phosphorylation and growth of tumors

Ishida, S.
•
Andreux, P.
•
Poitry-Yamate, C.  
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2013
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)

Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment.

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Type
research article
DOI
10.1073/pnas.1318431110
Web of Science ID

WOS:000327390400084

Author(s)
Ishida, S.
Andreux, P.
Poitry-Yamate, C.  
Auwerx, J.  
Hanahan, D.  
Date Issued

2013

Publisher

National Academy of Sciences

Published in
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)
Volume

110

Issue

48

Start page

19507

End page

12

Subjects

CIBM-PET

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
CIBM  
CMSO  
LISP  
Available on Infoscience
November 24, 2013
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/97209
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