P120ctn and P-Cadherin but Not E-Cadherin Regulate Cell Motility and Invasion of DU145 Prostate Cancer Cells

Sandra Kümper,Anne J Ridley

doi:10.1371/journal.pone.0011801

Abstract

BackgroundAdherens junctions consist of transmembrane cadherins, which interact intracellularly with p120ctn, ß-catenin and α-catenin. p120ctn is known to regulate cell-cell adhesion by increasing cadherin stability, but the effects of other adherens junction components on cell-cell adhesion have not been compared with that of p120ctn.Methodology/Principal FindingsWe show that depletion of p120ctn by small interfering RNA (siRNA) in DU145 prostate cancer and MCF10A breast epithelial cells reduces the expression levels of the adherens junction proteins, E-cadherin, P-cadherin, ß-catenin and α-catenin, and induces loss of cell-cell adhesion. p120ctn-depleted cells also have increased migration speed and invasion, which correlates with increased Rap1 but not Rac1 or RhoA activity. Downregulation of P-cadherin, β-catenin and α-catenin but not E-cadherin induces a loss of cell-cell adhesion, increased migration and enhanced invasion similar to p120ctn depletion. However, only p120ctn depletion leads to a decrease in the levels of other adherens junction proteins.Conclusions/SignificanceOur data indicate that P-cadherin but not E-cadherin is important for maintaining adherens junctions in DU145 and MCF10A cells, and that depletion of any of the cadherin-associated proteins, p120ctn, ß-catenin or α-catenin, is sufficient to disrupt adherens junctions in DU145 cells and increase migration and cancer cell invasion.

Highlights

During metastasis, cancer cells commonly gain the ability to migrate and invade tissues by regulating their interaction with other cells and their extracellular environment
To investigate the effects of p120ctn on cell-cell adhesion, we compared the effects of p120ctn depletion in two different cell lines that have adherens junctions, the human prostate cancer cell line DU145 and the human mammary epithelial cell line MCF10A
DU145 and MCF10A cells formed cell-cell contacts and expressed both E- and P-cadherin, which localized to cell-cell contacts (Fig. 1A, B)

Summary

Introduction

Cancer cells commonly gain the ability to migrate and invade tissues by regulating their interaction with other cells and their extracellular environment. P120ctn affects the activity of the small GTPases RhoA, Rac and Cdc in some cell types [24],[25],[26],[27], which play a central role in regulating cytoskeletal dynamics, the formation and maintenance of adherens junctions and cell migration [28],[29]. We have knocked down p120ctn in DU145 prostate cancer cells and MCF10A mammary epithelial cells, both of which normally have adherens junctions containing E-cadherin and P-cadherin. In both cell types depletion of p120ctn leads to disruption of cell-cell contacts, downregulation of adherens junction proteins and increased cell motility. For the first time we have knocked down cadherins as well as catenins and show that P-cadherin, b-catenin and a-catenin but not E-cadherin depletion mimic the effects of p120ctn suppression and lead to a loss of cell-cell contacts and enhanced invasion

Results

Discussion

Materials and Methods