Abstract C49: Tissue tranglutaminase regulates β-catenin signaling in ovarian cancer cells

Abstract

Abstract Background: Tissue transglutaminase (TG2) is a multifunctional enzyme involved in protein crosslinking and cell adhesion to fibronectin (FN). In cancer, TG2 induces epithelial-to-mesenchymal transition (EMT) contributing to metastasis. As cadherins bind β-catenin at cell-cell junctions, disruption of adherens junctions destabilizes cadherin-catenin complexes. The goal of the present study was to analyze whether and how TG2 interacts with and regulates β–catenin signaling in ovarian cancer (OC) cells. Methods: Western blotting, immuno-fluorescence and immunohistochemistry measured TG2 and β-catenin expression in OC cells and human tumors. B-catenin function was analyzed by TCF/LEF1 promoter reporter assay and Q-RT-PCR based quantification of mRNA levels for target genes (c-myc and cyclin D1). Protein-protein interaction was analyzed by co-immunoprecipitation and confocal microscopy. Cell proliferation was measured by MTT assay. Results: We observed a significant correlation between TG2 and β-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/β-catenin signaling, as evidenced by enhanced β-catenin transcriptional activity, inducing transcription of target genes cyclin D1 and c-Myc. By promoting integrin-mediated cell adhesion to FN, TG2 associates with and recruits c-Src, which in turn phosphorylates β-catenin at Tyr654, releasing it from E-cadherin, and rendering it available for transcription regulation. Ultimately the TG2—FN interaction stimulates OC cell proliferation by enhancing β-catenin signaling. Conclusions: Our data show that TG2 regulates β-catenin expression and function in OC cells and define a c-Src dependent mechanism through which this occurs. We posit that the TG2-FN interaction initiates this process and could be a new cancer target. Citation Format: Salvatore Condello, Liyun Cao, Daniela Matei. Tissue tranglutaminase regulates β-catenin signaling in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C49.