Insulin-like modulation of AKT/FoxO signaling by copper ions is independent of insulin receptor

Ingrit Hamann, Kerstin Petroll, Larson Grimm, Andrea Hartwig, Lars Oliver Klotz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)42-50
Number of pages9
JournalArchives of Biochemistry and Biophysics
Publication statusPublished - 15 Sept 2014
Externally publishedYes


  • Akt
  • Copper ions
  • FoxO
  • Hepatoma cells
  • Insulin signaling
  • Linsitinib
  • PTPase (protein tyrosine phosphatase)
  • ROS


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