MAPKs in prostate cancer epithelial mesenchymal plasticity 1 The MAP Kinases p38 and ERK are Involved in Hepatocyte-mediated Phenotypic Switching in Prostate Cancer Cells Bo Ma, Alan Wells Department of Pathology, University of Pittsburgh and Pittsburgh VAMC Pittsburgh PA, USA 15261 *Running title: MAPKs in prostate cancer epithelial mesenchymal plasticity To whom correspondence should be addressed: Alan wells, Department of pathology, University of Pittsburgh and Pittsburgh VAMC, 3550 Terrace St, Scaife Hall S713, Pittsburgh, PA,USA, Tel: (412) 624-0973; Fax: (412) 624-8946; E-mail: wellsa@upmc.edu Key words: Metastasis, Epithelial to Mesenchymal Transition, EGF Receptor, Mesenchymal to Epithelial reverting Transition, Cell Survival, Chemotherapy, E-cadherin Background: Epithelial mesenchymal phenotypic switching enables cancers to seed and survive in metastatic sites. Results: Both p38 and ERK1/2 MAP kinases need to be inhibited to allow for an epithelial reversion but activated to provide survival advantage in the face of chemotherapy. Conclusion: Distinct p38/ERK signaling outcomes are involved in hepatocytes-mediated MErT and tumor cells survival. Significance: Provides insights to understand approaches to p38α or ERK1/2 activity regulation for cancer therapy. ABSTRACT The greatest challenge for the seeding of cancer in metastatic sites is integration into the ectopic micro-environment despite the lack of an orthotopic supportive environment and presence of pro-death signals concomitant with a localized ‘foreign-body’ inflammatory response. In this metastatic location, many carcinoma cells display a reversion of the epithelial-to-mesenchymal transition (EMT) that marks dissemination in the primary tumor mass. This mesenchymal to epithelial reverting transition (MErT) is thought to help seeding and colonization by protecting against cell death. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin via abrogation of autocrine EGFR signaling pathway in prostate cancer (PCa) cells and that this confers a survival advantage. Herein, we show that hepatocytes educate PCa to undergo MErT by modulating the activity of p38 and ERK1/2. Hepatocytes inhibited p38 and ERK1/2 activity in prostate cancer cells which allowed E-cadherin re- expression. Introduction of constitutively active MEK6 and MEK1 to DU145 cells cocultured with hepatocytes abrogated E-cadherin re- expression. At least a partial phenotypic reversion can be achieved by suppression of p38 and ERK1/2 activation in DU145 cells even in the absence of hepatocytes. Interestingly, these MAP kinase activities were also triggered by re-expressed E-cadherin leading to p38 and ERK1/2 activity in PCa cells; these signals provide protection to PCa cells upon challenge with chemotherapy and cell-death inducing cytokines. We propose that distinct p38/ERK pathways are related to E-cadherin levels and function downstream of E-cadherin allowing, respectively for hepatocyte-mediated MErT and tumor cell survival in the face of death signals. INTRODUCTION Metastasis is the main cause of death in most cancers. It has been suggested that this complex metastatic cascade could be conceptually organized and simplified into two major phases: (i) physical translocation of a cancer cell from the primary tumor to the microenvironment of a distant tissue and then (ii) colonization(1).Therefore, understanding the many molecules and processes leading to successful colonization may lead to effective therapies for http://www.jbc.org/cgi/doi/10.1074/jbc.M113.540237 The latest version is at JBC Papers in Press. Published on March 11, 2014 as Manuscript M113.540237 Copyright 2014 by The American Society for Biochemistry and Molecular Biology, Inc. by guest on November 4, 2016 http://www.jbc.org/ Downloaded from