title: Insulin-like modulation of Akt/FoxO signaling by copper ions is independent of insulin receptor.
abstract: Copper ions are known to induce insulin-like effects in various cell lines, stimulating the phosphoinositide 3'-kinase (PI3K)/Akt signaling cascade and leading to the phosphorylation of downstream targets, including FoxO transcription factors. The aim of this work was to study the role of insulin- and IGF1-receptors (IR and IGF1R) in insulin-like signaling induced by copper in HepG2 human hepatoma cells. Cells were exposed to Cu(II) at various concentrations for up to 60 min. While Akt and FoxO1a/FoxO3a were strongly phosphorylated in copper- and insulin-treated cells at all time points studied, only faint tyrosine phosphorylation of IR/IGF1R was detected in cells exposed to Cu(II) by either immunoprecipitation/immunoblot or by immunoblotting using phospho-specific antibodies, whereas insulin triggered strong phosphorylation at these sites. Pharmacological inhibition of IR/IGF1R modestly attenuated Cu-induced Akt and FoxO phosphorylation, whereas no attenuation of Cu-induced Akt activation was achieved by siRNA-mediated IR depletion. Cu(II)-induced FoxO1a nuclear exclusion was only slightly impaired by pharmacological inhibition of IR/IGF1R, whereas insulin-induced effects were blunted. In contrast, genistein, a broad-spectrum tyrosine kinase inhibitor, at concentrations not affecting IR/IGF1R, attenuated Cu(II)-induced Akt phosphorylation, pointing to the requirement of tyrosine kinases other than IR/IGF1R for Cu(II)-induced signaling.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ingrit
authors.initials: I
authors.lastname: Hamann
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Petroll
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Larson
authors.initials: L
authors.lastname: Grimm
authors.affiliation: Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartwig
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller Universität Jena, Germany. Electronic address: lars-oliver.klotz@uni-jena.de.
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Klotz
mesh_terms: D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D003300:Copper; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases
keywords: Akt; Copper ions; FoxO; Hepatoma cells; Insulin signaling; Linsitinib; PTPase (protein tyrosine phosphatase); ROS