Bioavailable copper modulates oxidative phosphorylation and growth of tumors.
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.
Swiss Institute for Experimental Cancer Research and Laboratory for Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, School of Life Sciences, and Biomedical Imaging Center, Institute of Physics of Biological Systems, Swiss Federal Institute of Technology Lausanne, CH-1015 Lausanne, Switzerland.
Seiko
S
Ishida
Pénélope
P
Andreux
Carole
C
Poitry-Yamate
Johan
J
Auwerx
Douglas
D
Hanahan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D015153:Blotting, Western; D003300:Copper / Q000633:toxicity*; D017931:DNA Primers / Q000235:genetics; D060766:Drinking Water / Q000032:analysis*; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000503:physiopathology*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D049268:Positron-Emission Tomography; D060888:Real-Time Polymerase Chain Reaction; D012119:Respiration; D059016:Tumor Microenvironment / Q000502:physiology*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D017931:DNA Primers; D060766:Drinking Water; D014874:Water Pollutants, Chemical; D003300:Copper; D000255:Adenosine Triphosphate
Warburg effect; cancer metabolism; mitochondria; pancreatic neuroendocrine tumor; tumor energetics