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

Nathália Villa Dos Santos,Alexandre Hiroaki Kihara,Andreza Cândido Matias,Giselle Cerchiaro,Guilherme Shigueto Vilar Higa

doi:10.1155/2015/162876

Nathália Villa Dos Santos, Alexandre Hiroaki Kihara + Show 3 more

Open Access

https://doi.org/10.1155/2015/162876

Copy DOI

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.

Highlights

Recent advances in biochemical tools have highlighted the extraordinary array of functions of Cu in living organisms [1]
Cu is involved in redox reactions that generate intracellular reactive oxygen species (ROS), mainly by Fenton reaction, and a number of reports point to a relationship between Cu, ROS production, and cancer development [10, 11], and recently the role of Cu metabolism in resistance of cancer cells to cisplatin [12,13,14]
On the basis of concentration-dependent studies (Figure 1), proliferation of MCF10A was not observed at concentrations above 75.0 μM CuSO4 after 24 hr of incubation (Figure 1(a)), but cell viability was significantly reduced after 48 hr (Figure 1(b)) when levels of Cu were equal to or greater than 200.0 μM

Summary

Introduction

Recent advances in biochemical tools have highlighted the extraordinary array of functions of Cu in living organisms [1]. A critical factor in the development of cancer is angiogenesis, which endows continuous supplying of nutrients, growth factors, and signaling agents to malignant tissue [4,5,6,7] This angiogenic response in tumor is stimulated by ceruloplasmin, the plasma Cu-carrier [6, 8, 9]. The redox status of cells is influenced by the homeostasis of reactive species, since ROS might act as secondary messengers in the regulation of pathways associated with cell proliferation, differentiation, and apoptosis [15, 16] Based on these findings, some studies suggested that elevated Cu levels and increased oxidative stress may be used in selective cancer therapy [17, 18]; the effect of Cu-stimulation in cell proliferation

Objectives

Methods

Results

Conclusion