Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells

BACKGROUND: The class 1 carcinogen cadmium (Cd(2+)) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis. RESULTS: We investigated Wnt signaling after Cd(2+)-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd(2+ )(25 μM, 3-9 h) caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd(2+ )reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd(2+), electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd(2+). Overexpression of wild-type and mutant TCF4 confirmed Cd(2+)-induced Wnt signaling. Wnt signaling elicited by Cd(2+ )was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd(2+ )toxicity. Cd(2+ )also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability. CONCLUSIONS: Cd(2+ )induces Wnt signaling in PTC. Hence, Cd(2+ )may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.