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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.

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