Abstract
In epithelial cells, β-catenin is localized at cell-cell junctions where it stabilizes adherens junctions. When these junctions are disrupted, β-catenin can translocate to the nucleus where it functions as a transcriptional cofactor. Recent research has indicated that PGE2 enhances the nuclear function of β-catenin through cyclic AMP. Here, we aim to study the role of the cyclic AMP effector Epac in β-catenin activation by PGE2 in non-small cell lung carcinoma cells.We show that PGE2 induces a down-regulation of E-cadherin, promotes cell migration and enhances β-catenin translocation to the nucleus. This results in β-catenin-dependent gene transcription. We also observed increased expression of Epac1. Inhibition of Epac1 activity using the CE3F4 compound or Epac1 siRNA abolished the effects of PGE2 on β-catenin. Further, we observed that Epac1 and β-catenin associate together. Expression of an Epac1 mutant with a deletion in the nuclear pore localization sequence prevents this association. Furthermore, the scaffold protein Ezrin was shown to be required to link Epac1 to β-catenin.This study indicates a novel role for Epac1 in PGE2-induced EMT and subsequent activation of β-catenin.
Highlights
Non-small cell lung carcinoma (NSCLC) is the most common variety of lung cancer and is the leading cause of cancer related deaths worldwide
This study indicates a novel role for Epac1 in prostaglandin E2 (PGE2)-induced epithelial-tomesenchymal transition (EMT) and subsequent activation of β-catenin
After scratch-wounding of a confluent monolayer, PGE2 treatment resulted in decreased E-cadherin protein expression, primarily in cells on an edge, while cells that were fully incorporated in the epithelial structure were less affected (Figure 1C-1D)
Summary
Non-small cell lung carcinoma (NSCLC) is the most common variety of lung cancer and is the leading cause of cancer related deaths worldwide. One of the major causes for mortality is dissemination [1, 2] whereby, early in the metastatic cascade, carcinoma cells gradually lose their epithelial phenotype and acquire a motile, mesenchymal phenotype. This process is known as epithelial-tomesenchymal transition (EMT) [3]. In NSCLC cells, EMT can be induced by a variety of growth factors and other molecular mediators, including prostaglandin E2 (PGE2) [4,5,6,7,8]. PGE2 is a potent inflammatory mediator produced by cyclooxygenase-2 (COX-2), whose levels are often found to be increased in many cancers, including lung carcinoma [9]. The use of selective COX-2 inhibitors has raised multiple concerns regarding its safety of long-term use in clinical trials [11]
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