Abstract LB-301: Copper chelation therapy suppresses tumor growth by inhibiting mitochondrial ATP production in tumors.

Abstract Through our yeast genetic screen, we have previously identified the copper transporter Ctr1 as a major mediator of cisplatin uptake in mammals (1), and have subsequently shown in a transgenic mouse model of human cervical cancer that reducing systemic copper levels with a copper chelator, which is clinically used to treat patients with copper disorders, results in enhanced uptake of cisplatin selectively in tumors but not in normal, non-cancerous tissues (2), suggesting that tumors are particularly sensitive to changes in copper levels. In fact, environmental copper exposure has been associated with cancer risk in humans, although the nature of its effects on tumourigenesis remains unclear. Using a transgenic mouse model of pancreatic islet carcinoma, here we demonstrate that chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum level allowed in our drinking water, accelerate tumor growth by stimulating proliferation of cancer cells. Conversely, reducing systemic copper with a chelating drug resulted in inhibition of tumor growth and cancer cell proliferation. Under copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis. The anti-proliferative effect of copper chelation was not observed in cells deficient in cytochrome c oxidase activity, but was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors, and exhibited lower activity of cytochrome c oxidase and higher glucose uptake, suggesting that a shift towards glycolytic metabolism observed in tumors even in the presence of ample oxygen (Warburg effect) may in part reflect insufficient copper bioavailability in the tumour microenvironment. Our work identifies copper as a rate-limiting element for tumor growth and mitochondrial ATP production, and provides experimental evidence that explains the association between copper intake levels and cancer implicated in previous epidemiological and clinical studies. These findings offer a novel concept of limiting intake levels of this environmental factor as a strategy for cancer prevention and treatment. Citation Format: Seiko Ishida, Pénélope Andreux, Johan Auwerx, Douglas Hanahan. Copper chelation therapy suppresses tumor growth by inhibiting mitochondrial ATP production in tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2013-LB-301