Abstract
BackgroundThe class 1 carcinogen cadmium (Cd2+) 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.ResultsWe investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd2+ (25 μM, 3-9 h) caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ 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 Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ 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.ConclusionsCd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.
Highlights
The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer
We confirmed that micromolar Cd2+ concentrations decrease trans-epithelial resistance of cultured WKPT-0293 Cl.2 rat kidney proximal tubule cells (PTC) within 1 hour of exposure which correlated with a decrease of membrane-associated E-cadherin and βcatenin and an increase of c-Myc and Abcb1 mRNA after 3 hours [17]
This was corroborated by confocal immunofluorescence microscopy of Cd2+ treated PTC which exhibited a more diffuse β-catenin distribution in the cytoplasm and nucleus compared to the controls where β- catenin was predominately found at the cell borders (Fig. 1B)
Summary
The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. One early event associated with cadmium ion (Cd2+) nephrotoxicity is the alteration of the properties of AJs and TJs, most likely due to Ca2+ displacement, which causes disruption of the homophilic E-cadherin interaction [15]. This causes a loss of integrity in the cell-cell adhesion belt and disassembly of TJs with a concomitant decrease in the trans-epithelial resistance and increased paracellular permeability (reviewed in [16]). The data demonstrate that Cd2+ induces Wnt signaling in PTC to upregulate proliferation and survival genes
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