Nickel and copper ion-induced stress signaling in human hepatoma cells: analysis of phosphoinositide 3′-kinase/Akt signaling

Abstract

Nickel compounds may act as carcinogens, affecting both initiation and promotion stages of carcinogenesis due, in large parts, to their capability of inducing DNA damage and of modulating cellular signaling cascades known to affect cellular proliferation, respectively. We have previously demonstrated that the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is stimulated in cells exposed to copper ions, resulting in phosphorylation and nuclear exclusion of FoxO transcription factors. Here, human hepatoma cells were exposed to nickel or copper ions, followed by comparative analysis of PI3K/Akt-dependent signaling. Exposure of hepatoma cells to copper ions resulted in extensive oxidation of cellular glutathione, while no such effect was detected with nickel ions. Similarly, copper ions were more than 100-fold more toxic to cells than nickel, as deduced from analyses of colony forming abilities. Despite this lack of oxidative and cytotoxic action, exposure of hepatoma cells to Ni(2+) resulted in a significant activation of Akt that was abrogated by inhibitors of PI3K. Interestingly, activation of Akt--although coincident with a phosphorylation of Akt substrates, such as glycogen synthase kinase-3--did not result in significant nuclear exclusion of FoxO1a. In line with this finding, no significant modulation of the activity of a FoxO-responsive promoter construct was observed in cells exposed to nickel ions. In summary, exposure of HepG2 human hepatoma cells to nickel ions results in stimulation of the Ser/Thr kinase Akt in a PI3K-dependent fashion, activation most likely being independent of oxidative processes. In sharp contrast to copper ions, nickel-induced Akt activation is not propagated further downstream to FoxO-dependent signaling beyond the phosphorylation of FoxO1a and 3a.

Genotoxic effects of old landfill leachate on HepG2 cells after nitration/ultrafiltration/reverse osmosis membrane treatment process

“…genotoxicity could be induced by the relatively high concentrations of heavy metals (Ni, Pb, Cr, Cd, Mn), high concentration of organic biorefractory compounds (COD, color) and/or nitrogen species (Adamsson et al, 1998;Gajski et al, 2012;Rodrigues et al, 2007). Some studies have reported that the presence of dioxins, polychlorinated biphenyls, polyaromatic hydrocarbons (not measured in the present study) and PAEs could also impair DNA integrity (Ernst et al, 1994;Kleinsasser et al, 2000;Toufexi et al, 2013), and the possible mechanism of leachateinduced DNA damage might be related with its ability to enhance oxidative stress caused by several xenobiotics (Bertoldi et al, 2012;Eckers et al, 2009;Patlolla et al, 2009;Shim et al, 2017). On the other hand, leachate absorption into HepG2 cells could change the pH outside and within cells, which might change the structures of DNA (Li et al, 2010).…”

Cytotoxicity of Metal Ions Released from Nitinol Alloys on Endothelial Cells

“…Moreover, Ni +2 can act as an antagonist to essential metal ions like Mg +2 , Ca +2 , and Zn +2 and disturb the biological processes (Ref 4). Similarly, Cu +2 ions also induce oxidative stress within the cell, which result in severe loss of cell viability (Ref 8). …”

Heavy metal ion-induced insulin-mimetic signaling

“…19 Several transition metal ions were tested for their potency in stimulating Akt in HeLa and other cells, resulting in the finding that Cu(II) and Zn(II) are the most potent stimulators of Akt, followed by Cd(II) 19 and Ni(II), which was recently shown to be capable of causing weak, but significant, Akt activation in HepG2 human hepatoma cells but, for reasons yet unknown, not in other cell types. 20 Neither Mn(II), Fe(II) nor Co(II) stimulated Akt activity under these conditions. 19 A substantial activation of Akt generally appears to be achieved with approximately 10-fold lower concentrations of Cu(II) than Zn(II), with [Cu 2+ ] as low as 3 µM eliciting Akt activation in fibroblasts.…”

“…3) nor any attenuation of G6Pase promoter activity. 20 The insulin receptor/PI3K/Akt/FoxO axis that links insulin binding to target cells to transcriptional regulation of gene expression in these cells is a highly conserved cascade, found in lower organisms such as Caenorhabditis elegans or Drosophila melanogaster. 29 Similarly, the cellular response to Cu(II) appears to be highly conserved as the exposure of C. elegans worms to Cu(II) in their growth media causes a nuclear exclusion of the FoxO ortholog, DAF-16 (DAF, abnormal dauer formation).…”