Copper Uptake in Mammary Epithelial Cells Activates Cyclins and Triggers Antioxidant Response

Abstract

The toxicologic effects of copper (Cu) on tumor cells have been studied during the past decades, and it is suggested that Cu ion may trigger antiproliferative effects in vitro. However, in normal cells the toxicologic effects of high exposures of free Cu are not well understood. In this work, Cu uptake, the expression of genes associated with cell cycle regulation, and the levels of ROS production and related oxidative processes were evaluated in Cu-treated mammary epithelial MCF10A nontumoral cells. We have shown that the Cu additive is associated with the activation of cyclin D1 and cyclin B1, as well as cyclin-dependent kinase 2 (CDK2). These nontumor cells respond to Cu-induced changes in the oxidative balance by increase of the levels of reduced intracellular glutathione (GSH), decrease of reactive oxygen species (ROS) generation, and accumulation during progression of the cell cycle, thus preventing the cell abnormal proliferation or death. Taken together, our findings revealed an effect that contributes to prevent a possible damage of normal cells exposed to chemotherapeutic effects of drugs containing the Cu ion.

Antitumor activity of resveratrol is independent of Cu(II) complex formation in MCF-7 cell line

“…Two copper concentrations and Rsv are capable of inducing ROS separately as reported by Dos Santos and co-workers (2015). 32 These results confirm that Rsv and Cu (II) do not have synergistic effect of action in producing ROS or promoting cell death, revealing that there is no formation of Rsv-Cu (II) complex in in vitro model for MCF-7 cell line. A putative explanation could be that pH is not adequate for complex formation.…”

“…Enriched cells with copper showed no significant decrease in the viability. In contrast, cells with Cu and Rsv revealed a decrease in apoptosis promoted by Rsv alone values found for cells enriched with 10 and 50 lM of CuSO 4 and treated with Rsv were of 3.07 (±16)% and 2.72 (±13)% respectively, 31,32 suggesting a protective effect of Rsv against apoptosis. Two copper concentrations and Rsv are capable of inducing ROS separately as reported by Dos Santos and co-workers (2015).…”

“…2A). However, cells enriched with copper showed no significant decrease in the viability, while cells with Cu and Rsv revealed a decrease in apoptosis promoted by Rsv alone, 31,32 suggesting a protective effect of Rsv against apoptotic death.…”