Cadherin Switching and Activation of β-Catenin Signaling Underlie Proinvasive Actions of Calcitonin-Calcitonin Receptor Axis in Prostate Cancer

Abstract

Prostate cancer (PC) 2 is the most commonly diagnosed cancer and the second leading cause of cancer deaths in men in the United States (1, 2). Although androgen ablation therapy is effective in men with advanced disease for some time, the disease subsequently progresses to the androgen-independent stage. The population of prostate cells expressing neuroendocrine factors such as calcitonin (CT) also increases during this progression (3-5). At this stage, the disease is metastatic and chemoresistant. Present evidence suggests that cancer metastasis is usually preceded by the disruption of normal cell-cell adhesion and the loss of integrity of the primary tumor site (6, 7). This process may include several genetic, molecular, and morphological changes characterized by epithelial-to-mesenchymal transition (EMT) (8 -10). The EMT is characterized by the loss of cell polarity, altered cell-cell and cell-matrix adhesion, and acquisition of migratory, mesenchymal phenotype. Other reported changes include down-regulation of E-cadherin, induction of N-cadherin, release of ␤-catenin from junctional complexes, and its translocation to the nucleus (11-13). However, the precise molecular mechanisms associated with this process are obscure.Several growth factors, including hepatocyte growth factor, transforming growth factor-␤, vascular endothelial growth factor, and epidermal growth factor, have been reported to induce EMT in tumor cell lines (14 -16). We have shown that the expression of CT and its G protein-coupled receptor (CTR) is remarkably higher in advanced PCs, and the CT-CTR autocrine axis is a potent stimulator of PC cell tumorigenicity, invasion, and metastasis (4,(17)(18)(19). Although CT-stimulated increase in the motility and invasion of PC cells may be mediated by CTstimulated secretion of matrix metalloproteinases and urokinase-type plasminogen activator, the precise molecular mechanisms preceding these CTR actions remain to be elucidated (18,20). We tested the hypothesis that CT induces biochemical and morphological changes associated with EMT to increase the invasiveness of PC cells.Our results indicate that activation of the CT-CTR autocrine axis in prostate cancer cells induced several changes associated with EMT such as remodeling of tight and adherens junctions, cadherin switching, and activation of WNT/␤-catenin signaling. In contrast, the silencing of the CT-CTR axis reversed this process. Moreover, cyclic AMP-dependent protein kinase (PKA) plays a key role in this CT-CTR-mediated process. This is the first study demonstrating the action of prostate CTR on junctional complexes and WNT/␤-catenin signaling of PC cell lines.

HPV-16 E6/E7 promotes cell migration and invasion in cervical cancer via regulating cadherin switch in vitro and in vivo

“…Presently, several mechanisms for induction of cadherin switch in tumor cells have been reported, including transcriptional control of inhibitor of differentiation-1 (Id-1) [21] and slug [22], post-transcriptional control of the cadherin/catenin complex [23], regulation of transforming growth factor beta (TGF-b) [24] and gonadotropin-releasing hormone (GnRH) [25] or regulation of P13 K/PTEN [26] pathway and Wnt/b-catenin [27] pathway. Each of these mechanisms has been implicated in various tumor types.…”

Unraveling the Role of FOXQ1 in Colorectal Cancer Metastasis

“…E-cadherin is invariably almost always downregulated during EMT with a concomitant switch to a mesenchymal cadherin that may, or may not be associated with an overt phenotypic mesenchymal transformation (30,31). This cadherin switch is modulated by a number of transcriptional regulators, one of which is Twist1 (32).…”

Tissue inhibitor of metalloproteinase 2 inhibits activation of the β-catenin signaling in melanoma cells

“…41,42 Cancer metastasis may include morphological changes characterized by epithelial-tomesenchymal transition with down-regulation of E-cadherin and induction of Ncadherin, release of β-catenin from junctional complexes. 43 The loss of E-cadherin may result in a reduction in N-cadherin-mediated adhesiveness and facilitate the migration of tumor cells across the junctions. Rearrangements and defects of Ecadherin adhesions were found in many carcinomas.…”