P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation

Abstract

Cadherins belong to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity. They play a major role in the development and homeostasis of epithelial architecture. Recently, it has become more and more evident that P-cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical cadherins, P-cadherin, E-cadherin and N-cadherin. This cell line was transfected with full-length P-cadherin (PCI52_PC). After overexpression of P-cadherin, PCI52_PC gained an epithelial-like brickstone morphology in contrast to the mock-transfected cells with a spindle-shaped mesenchymal morphology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells compared with a significantly reduced nuclear staining and translocation to the cytoplasm in P-cadherin-overexpressing cells. Interestingly, the effects triggered by P-cadherin overexpression could be reversed by transfecting the cells with an antisense P-cadherin plasmid construct. Additional investigations showed a reexpression of E-cadherin in all P-cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-cadherin-overexpressing cell lines showed activated GSK-3beta that phosphorylated Snail leading to its cytoplasmic translocation. In summary, our results reveal P-cadherin as one major component in reconfiguring mesenchymal cells with epithelial features by triggering GSK-3beta-mediated inactivation and cytoplasmatic translocation of Snail in OSCC.

Induction of type XVI collagen expression facilitates proliferation of oral cancer cells

“…Additionally, neo-expression of integrin alpha1beta1 was verified in OSCC cells after snail transfection (Takkunen et al, 2008). In line with these data, we have observed high snail expression levels in all our cell lines (Bauer et al, 2009). These results imply that signalling of type XVI collagen could be directed via integrins apha1beta1 in OSCC.…”

P-cadherin role in normal breast development and cancer

“…After P-cadherin overexpression, cells gained an epithelial-like morphology, with Snail translocation to the cytoplasm. Analysing the signalling mechanism behind it, they found glycogen-synthase-kinase-3b (GSK-3b) bound to Snail, as well as an increase in activated GSK-3b that phosphorylated Snail leading to its cytoplasmic translocation (Bauer et al, 2009). These same authors also showed that Slit-2, a secreted ECM glycoprotein that acts as a molecular guidance cue in cellular migration, facilitates the interaction of P-cadherin with Robo-3, its receptor, and inhibits cell migration in oral squamous cell carcinoma cell line models (Bauer et al, 2011) (Fig.…”

Post-translational modifications of EMT transcriptional factors in cancer metastasis

“…In an investigation to determine the signaling pathway underlying E-cadherin, Bauer et al observed the phenomenon that the kinase GSK-3β interacted with and phosphorylated Snail. Therefore, Snail was blocked in the cytoplasm and inactivated in oral squamous cell carcinoma [22]. Interestingly, Snail function was dual modulated by GSK-3β-dependent phosphorylation.…”