Abstract A59: Protein kinase CK2 regulates β-catenin association to E-cadherin and hence viability and invasion of colorectal cancer cells

Abstract

Abstract The key factor in the canonical Wnt pathway is β-catenin which also functions in cell-cell adhesion forming a complex with E-cadherin at the cell surface. Activation of the canonical Wnt pathway is linked to the release of β-catenin from the cell surface, its cytoplasmic stabilization and nuclear import, followed by increased transcriptional activity on genes normally linked to cancer progression, such as survivin and cyclin D1. We already described that caveolin-1 is a member of this complex (termed CEB for caveolin-1/E-cadherin/β-catenin) which inhibits β-catenin transcriptional activity thereby acting as a tumor suppressor. Conversely, protein kinase CK2 is abnormally elevated in a wide variety of cancers, promoting progression by regulating oncogene and tumor suppressor proteins, but also promoting an elevated β-catenin activity. We already demonstrated that cyclooxygenase-2 (COX-2) is a target of CK2 and its metabolite, prostaglandin E2 (PGE2), is key to up-regulate cell proliferation and apoptosis resistance. However, how CK2, PGE2, and caveolin-1 participate in the mechanism of CK2-mediated colorectal cancer progression is yet unknown. In this work, we hypothesize that CK2 promotes cancer progression by augmenting COX-2 expression and subsequently PGE2 production, which disrupts the putative CEB complex in an autocrine manner, leading to the release of β-catenin and increase of its nuclear activity. This was investigated by determining the presence of CEB complex in DLD-1 colon cancer cells (IP), as well as by evaluating the effect of either PGE2 or a CK2 inhibitor (TBB) on in vitro proliferation (MTS®), apoptosis (Caspase-Glo®) and invasiveness (wound-healing and matrigel assays) of these cancer cells. Our results suggest that the CK2-dependent autocrine production of PGE2 in DLD-1 colon cancer cells promotes the dissociation of caveolin-1 from the CEB complex at the cell surface, allowing β-catenin to be apparently phosphorylated (WB anti-P-antibodies) and released to the cytosol, which increments its nuclear import and transcriptional activity on cancer-related genes. Supported by ICGEB (CRP/CHI10-01) and FONDECYT (11070116, 1120132) grants to J.C.T. Citation Format: Roger Yefi, Eduardo Silva, Pablo Cabello, Ignacio Niechi, Hernan Huerta, Ricardo Armisen, Cristina Fernandez, Julio C. Tapia. Protein kinase CK2 regulates β-catenin association to E-cadherin and hence viability and invasion of colorectal cancer cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A59.