MP87-19 ETS RELATED GENE (ERG) DRIVEN ANDROGEN RECEPTOR AGGREGATION IS A KEY REGULATOR OF ENDOPLASMIC STRESS AND CELL SURVIVAL DURING PROSTATE CARCINOGENESIS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2017MP87-19 ETS RELATED GENE (ERG) DRIVEN ANDROGEN RECEPTOR AGGREGATION IS A KEY REGULATOR OF ENDOPLASMIC STRESS AND CELL SURVIVAL DURING PROSTATE CARCINOGENESIS Taduru Sreenath, Natallia Mikhalkevich, Shashwat Sharad, Rishita Gupta, Oluwatosin Diaro, Kevin Babcock, Charles Xavier, Ahmed Mohamed, Muhammad Jamal, Shyh-Han Tan, Albert Dobi, Gyorgy Petrovics, Isabell Sesterhenn, David McLeod, Inger Rosner, and Shiv Srivastava Taduru SreenathTaduru Sreenath More articles by this author , Natallia MikhalkevichNatallia Mikhalkevich More articles by this author , Shashwat SharadShashwat Sharad More articles by this author , Rishita GuptaRishita Gupta More articles by this author , Oluwatosin DiaroOluwatosin Diaro More articles by this author , Kevin BabcockKevin Babcock More articles by this author , Charles XavierCharles Xavier More articles by this author , Ahmed MohamedAhmed Mohamed More articles by this author , Muhammad JamalMuhammad Jamal More articles by this author , Shyh-Han TanShyh-Han Tan More articles by this author , Albert DobiAlbert Dobi More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , Isabell SesterhennIsabell Sesterhenn More articles by this author , David McLeodDavid McLeod More articles by this author , Inger RosnerInger Rosner More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2723AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Deregulated androgen receptor (AR) signaling due to either mutations or altered expression of the AR and its cofactors (activators or suppressors) has been identified as critical in prostate cancer development and progression. AR regulated oncogenic activation of Ets Related Gene (ERG) represents one of the most common and validated prostate cancer driver gene. In our recent studies using prostate specific ERG transgenic mouse prostate glands, we a observed novel morphological phenotypes of endoplasmic reticulum (ER) stress. Since AR was the critical regulator of ERG expression through TMPRSS2 promoter in human prostate cancer, the present study was aimed towards understanding the post-translational interactions between ERG and AR in ER stress and subsequent cell survival mechanisms in mouse and cell culture models. Understanding such mechanistic insights will potentially have major therapeutic implications. METHODS Histological phenotype in the mouse prostate glands were examined by light and electron microscopy. Cell culture models of LNCaP, HEK293 and COS7 cells were utilized to examine the AR aggregations, Co-IP and Proximal Ligation Assay in the presence and absence of ERG. Various domain deletions of AR were utilized to identify specific AR domain interactions with ERG and its contribution in AR aggregation. Luminal cell surface markers on the isolated mouse prostate glands and spontaneously immortalized mouse prostate epithelial cells from ERG transgenic mouse (MoE1) were analyzed by FACS analysis. RESULTS Co-expression of ERG and AR in LNCaP and COS-7 cells showed significant aggregation of AR in filter assays. Co-IP experiments and PLA assays in VCaP, LNCaP and HEK 293 cell revealed that ERG physically interacts with AR. Epithelial cells of ERG-Tg mouse prostates showed ~70% increase in CD49f (low) and Sca-1 (med) population with increased sphere formation capability and resistance to radiation induced cell death. Both epithelial cells grown into spheres and established MoE1 cells displayed increased CD49f (low) and significant increase in the EpCAM negative population. CONCLUSIONS Overall, our experiments demonstrate the mechanistic link that the physical interactions between ERG and AR initiate the ER stress in prostate epithelium through AR misfolding/aggregation. Our observation of ERG induced AR aggregation is one of the initial events that lead to ER stress to cell survival indicate a critical function for ERG in the etiology of prostate cancer initiation and progression. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1173 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Taduru Sreenath More articles by this author Natallia Mikhalkevich More articles by this author Shashwat Sharad More articles by this author Rishita Gupta More articles by this author Oluwatosin Diaro More articles by this author Kevin Babcock More articles by this author Charles Xavier More articles by this author Ahmed Mohamed More articles by this author Muhammad Jamal More articles by this author Shyh-Han Tan More articles by this author Albert Dobi More articles by this author Gyorgy Petrovics More articles by this author Isabell Sesterhenn More articles by this author David McLeod More articles by this author Inger Rosner More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...