Bioavailable copper modulates oxidative phosphorylation and growth of tumors

Abstract

Significance This paper describes the mechanism by which copper mediates the interplay between the two energy-producing pathways, respiration and glycolysis. Many tumors produce increased levels of lactate, even when oxygen abounds, reflecting aerobic glycolysis (“Warburg effect”), whereas most normal tissues solely use respiration. We demonstrate that reducing systemic copper with a chelating drug impaired mitochondrial energy metabolism and decreased ATP levels despite induction of glycolysis. We propose that the metabolic phenotype of tumors is modulated in part by variable levels of copper in tumor microenvironment. Our work identifies copper as a tumor promoter by demonstrating that chronic exposure to elevated levels of copper in drinking water—to the maximum allowed in public water supplies—accelerates tumor growth in mice.

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

“…In this study, we demonstrate that glutathione inhibits ERK phosphorylation through copper chelation, which is phenocopied by two other copper chelators, tetrathiomolybdate and trientine. Copper has been considered as a target for cancer therapy (42), but our results suggest it may not be a good target because copper chelators may enrich for cancer stem cells, whereas copper ionophores will increase cancer cell proliferation (43), neither of which is desired. The inhibition of ERK phosphorylation by glutathione is consistent with the effect of ATN-224, a specific copper chelator that is under clinical trials, which also inhibits ERK phosphorylation (44).…”

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

“…metal homeostasis | molecular imaging | luciferin | metabolic liver disease | copper C opper is an essential mineral for all higher organisms, serving as a redox-active cofactor for physiological processes, including respiration (1,2), antioxidant defense (3,4), neurotransmitter synthesis and metabolism (5), epigenetic modifications (6), and emerging roles in dynamic signaling networks (7)(8)(9)(10)(11). This same redox activity also poses a potential danger, requiring highly orchestrated regulation of copper pools to prevent oxidative stress and free radical damage events that are detrimental to health (12)(13)(14)(15)(16)(17)(18).…”

Health Effects of Metals in Particulate Matter

“…Copper levels in tumors affect cytochrome c oxidase activity, additional bioavailable copper facilitates increased production of ATP, which is consumed to fuel rapid proliferation of cancer cells. Thus, copper may not initiate transformation, but may stimulate proliferation of transformed cells by providing energy needed for cell-cycle progression as proposed Ishida and coworkers [42]. Additionally, copper ions are well suited to facilitate formation of ROS that can damage biomolecules, including DNA and chromatin.…”

“…Some studies have shown that serum copper levels are elevated in cancer patients and correlate with the severity of the disease and the response to therapies [42,43]. Copper-chelating drugs have been reported to have antiangiogenic activity in animal models.…”