The Desmosomal Armadillo Protein Plakoglobin Regulates Prostate Cancer Cell Adhesion and Motility through Vitronectin-Dependent Src Signaling

Carrie A Franzen,Viktor Todorović,Bhushan V Desai,Kathleen J Green,Salida Mirzoeva,Ximing J Yang,Jill C Pelling,Natasha Kyprianou

doi:10.1371/journal.pone.0042132

Abstract

Plakoglobin (PG) is an armadillo protein that associates with both classic and desmosomal cadherins, but is primarily concentrated in mature desmosomes in epithelia. While reduced levels of PG have been reported in localized and hormone refractory prostate tumors, the functional significance of these changes is unknown. Here we report that PG expression is reduced in samples of a prostate tumor tissue array and inversely correlated with advancing tumor potential in 7 PCa cell lines. Ectopically expressed PG enhanced intercellular adhesive strength, and attenuated the motility and invasion of aggressive cell lines, whereas silencing PG in less tumorigenic cells had the opposite effect. PG also regulated cell-substrate adhesion and motility through extracellular matrix (ECM)-dependent inhibition of Src kinase, suggesting that PG’s effects were not due solely to increased intercellular adhesion. PG silencing resulted in elevated levels of the ECM protein vitronectin (VN), and exposing PG-expressing cells to VN induced Src activity. Furthermore, increased VN levels and Src activation correlated with diminished expression of PG in patient tissues. Thus, PG may inhibit Src by keeping VN low. Our results suggest that loss of intercellular adhesion due to reduced PG expression might be exacerbated by activation of Src through a PG-dependent mechanism. Furthermore, PG down-regulation during PCa progression could contribute to the known VN-dependent promotion of PCa invasion and metastasis, demonstrating a novel functional interaction between desmosomal cell-cell adhesion and cell-substrate adhesion signaling axes in prostate cancer.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer mortality in the US [1], due mainly to the metastatic form of the disease [2]
Whether modulation of PG expression is responsible for any of the physiological and molecular events in PCa tumorigenesis has not yet been mechanistically studied. To address this issue and gain a better understanding of the relationship between PG expression and the extent of primary prostate tumor invasion, a PCa tissue microarray with 72 cores from 20 prostate cancer patients was analyzed for PG expression
In invasive T4 tumors there was an additional,30% decrease in PG (Fig. 1C). These findings indicated that PG expression was reduced and mislocalized in primary prostate cancer tissue compared to normal prostate tissue

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer mortality in the US [1], due mainly to the metastatic form of the disease [2]. The down-regulation of cell-cell adhesion molecules is one of the major steps in the process of local and distal prostate tumor invasion. Loss of the adherens junction molecule, P-cadherin, is an early event in most prostate cancers [6,7], while reduced expression of E-cadherin is connected with a more advanced and aggressive form of disease [8]. In spite of their expression in prostate tissues [9,10,11], little is known about the role of desmosomal cadherins in the initiation and progression of PCa

Methods

Results

Conclusion