Cadmium induces nuclear translocation of [beta]-catenin and increases expression of c-myc and Abcb1a in kidney proximal tubule cells

• Published in: Biometals Vol. 20; no. 5; p. 807
• Main Authors: Thévenod, Frank, Wolff, Natascha A, Bork, Ulrich, Lee, Wing-kee, Abouhamed, Marouan
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Nature B.V 01.10.2007
• Subjects: Apoptosis; Cadmium; Cadmium selenide; Carcinogenesis; Proteins; Translocation
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-006-9044-9

Cadmium (Cd^sup 2+^) induces renal proximal tubular (PT) damage, including disruption of the E-cadherin/β-catenin complex of adherens junctions (AJs) and apoptosis. Yet, chronic Cd^sup 2+^ exposure causes malignant transformation of renal cells. Previously, we have demonstrated that Cd^sup 2+^-mediated up-regulation of the multidrug transporter Abcb1 causes apoptosis resistance in PT cells. We hypothesized that Cd^sup 2+^ activates adaptive signaling mechanisms mediated by β-catenin to evade apoptosis and increase proliferation. Here we show that 50 µM Cd^sup 2+^, 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 Cd^sup 2+^ exposure, as measured by electric cell-substrate impedance sensing. Immunofluorescence microscopy demonstrates Cd^sup 2+^-induced decrease of E-cadherin at AJs and redistribution of β-catenin from the E-cadherin/β-catenin complex of AJs to cytosol and nuclei after 3 h. Immunoblotting confirms Cd^sup 2+^-induced decrease of E-cadherin expression and translocation of β-catenin to cytosol and nuclei of PT cells. RT-PCR shows Cd^sup 2+^-induced increase of expression of c-myc and of the isoform Abcb1a at 3 h. The data prove for the first time that Cd^sup 2+^ induces nuclear translocation of β-catenin in PT cells. We speculate that Cd^sup 2+^ activates β-catenin/T-cell factor signaling to trans-activate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells.[PUBLICATION ABSTRACT]