Cadmium induces nuclear translocation of beta-catenin and increases expression of c-myc and Abcb1a in kidney proximal tubule cells.
Cadmium (Cd2+) induces renal proximal tubular (PT) damage, including disruption of the E-cadherin/beta-catenin complex of adherens junctions (AJs) and apoptosis. Yet, chronic Cd2+ exposure causes malignant transformation of renal cells. Previously, we have demonstrated that Cd(2+)-mediated up-regulation of the multidrug transporter Abcb1 causes apoptosis resistance in PT cells. We hypothesized that Cd2+ activates adaptive signaling mechanisms mediated by beta-catenin to evade apoptosis and increase proliferation. Here we show that 50 microM Cd2+, which induces cell death via apoptosis and necrosis, also causes a decrease of the trans-epithelial resistance of confluent WKPT-0293 Cl.2 cells, a rat renal PT cell model, within 45 min of Cd2+ exposure, as measured by electric cell-substrate impedance sensing. Immunofluorescence microscopy demonstrates Cd(2+)-induced decrease of E-cadherin at AJs and redistribution of beta-catenin from the E-cadherin/beta-catenin complex of AJs to cytosol and nuclei after 3 h. Immunoblotting confirms Cd(2+)-induced decrease of E-cadherin expression and translocation of beta-catenin to cytosol and nuclei of PT cells. RT-PCR shows Cd(2+)-induced increase of expression of c-myc and of the isoform Abcb1a at 3 h. The data prove for the first time that Cd2+ induces nuclear translocation of beta-catenin in PT cells. We speculate that Cd2+ activates beta-catenin/T-cell factor signaling to trans-activate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells.
Thévenod
Frank
F
Department of Physiology & Pathophysiology, University of Witten/Herdecke, Stockumer Str. 12, D-58448 Witten, Germany. frank.thevenod@uni-wh.de
Wolff
Natascha A
NA
Bork
Ulrich
U
Lee
Wing-Kee
WK
Abouhamed
Marouan
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002104:Cadmium / Q000502:physiology*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D015820:Cadherins; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D002104:Cadmium