title: Copper is a potent inhibitor of both the canonical and non-canonical NFκB pathways.
abstract: Copper is an essential trace element that plays key roles in many metabolic processes. Homeostatic regulation of intracellular copper is normally tightly controlled, but deregulated copper levels are found in numerous metabolic and neurodegenerative diseases, as well as in a range of neoplasms. There are conflicting reports regarding the exact role of copper in the regulation of NFκB-responsive genes, specifically whether copper leads to increased activation of the NFκB pathways, or downregulation. Here we show that increased intracellular levels of copper, using the ionophore clioquinol, leads to a potent inhibition of NFκB pathways, induced by multiple distinct stimuli. Addition of copper to cells inhibits ubiquitin-mediated degradation of IκBα by preventing its phoshorylation by the upstream IKK complex. Intriguingly, copper-dependent inhibition of NFκB can be reversed by the addition of the reducing agent, N-acetylcysteine (NAC). These results suggest that the oxidative properties of excess copper prevent NFκB activation by blocking IκBα destruction, and that NFκB activity should be assessed in diseases associated with copper excess.
authors.affiliation: Department of Pathology; The University of Michigan Medical School; Ann Arbor, MI USA; Translational Oncology Program; The University of Michigan Medical School; Ann Arbor, MI USA.
authors.forename: Niall S
authors.initials: NS
authors.lastname: Kenneth
authors.affiliation: Translational Oncology Program; The University of Michigan Medical School; Ann Arbor, MI USA; Department of Pediatrics; The University of Michigan Medical School; Ann Arbor, MI USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Hucks
authors.affiliation: Department of Pathology; The University of Michigan Medical School; Ann Arbor, MI USA; Translational Oncology Program; The University of Michigan Medical School; Ann Arbor, MI USA; Graduate Program in Immunology; The University of Michigan Medical School; Ann Arbor, MI USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kocab
authors.affiliation: Department of Pathology; The University of Michigan Medical School; Ann Arbor, MI USA; Translational Oncology Program; The University of Michigan Medical School; Ann Arbor, MI USA.
authors.forename: Annie L
authors.initials: AL
authors.lastname: McCollom
authors.affiliation: Department of Pathology; The University of Michigan Medical School; Ann Arbor, MI USA; Translational Oncology Program; The University of Michigan Medical School; Ann Arbor, MI USA; Department of Internal Medicine; The University of Michigan Medical School; Ann Arbor, MI USA.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D007476:Ionophores; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051636:X-Linked Inhibitor of Apoptosis Protein; D000072000:NF-KappaB Inhibitor alpha; D003300:Copper; D007464:Clioquinol; D000111:Acetylcysteine
keywords: NFκB; clioquinol; copper; reactive oxygen species