Cadmium-induced DNA synthesis and cell proliferation in macrophages: The role of intracellular calcium and signal transduction mechanisms

Cd2+ exposure increases the risk of cancer in humans and animals. In this report, we have studied the effect of Cd2+ on signal transduction and Ca2+ mobilization in murine macrophages. At micromolar concentrations, Cd2+ significantly increased cell division as judged by [H-3]thymidine uptake and cell counts. Cd2+-treated cells continued to proliferate even after more than 4 weeks in culture. Cd2+ (1 muM) treatment induced a 1.5- to 2-fold increase in cytosolic free Ca2+, [Ca2+](i), which was transitory and/or oscillatory. The sources of this Ca2+ included both inositol 1,4,5-trisphosphate (IP3)-sensitive and -insensitive stores. Macrophage treatment with 1-(6-((17beta-3-methoxyestra-1,2,5(10)-triene17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), decreased Cd2+-induced formation of IP3 in a concentration-dependent manner (K-d similar to 2 muM). This caused a concomitant, partial decrease in the effect of Cd2+ on [Ca2+](i). Cd2+ itself crosses the macrophage membrane in pail via L-type Ca2+ channels, but it also interacts with a cell surface membrane protein(s) coupled to a pertussis toxin-sensitive G protein. Use of selective inhibitors of signal transduction and the quantitation of the levels of phosphorylated MAPK/ERK-activating kinase-1 (MEK1), extracellular signal-regulated kinase-1 (ERK1), and 2. p38 mitogen-activated protein kinase (MAPK) suggests that the effects of Cd are mediated by the p21(ras)-dependent MAPK, but not the phosphoinositide 3 (PI 3)-kinase signalling pathway. The effect of activating these pathways includes increased availability of the transcription factor NFkappaB as well as activation of the early genes c-fos and c-myc. (C) 2002 Elsevier Science Inc. All rights reserved.