MP84-10 ERG INDUCES ENDOPLASMIC RETICULUM STRESS (ER) AND UNFOLDED PROTEIN RESPONSE (UPR) TO INITIATE PROSTATE CANCER CARCINOGENESIS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2016MP84-10 ERG INDUCES ENDOPLASMIC RETICULUM STRESS (ER) AND UNFOLDED PROTEIN RESPONSE (UPR) TO INITIATE PROSTATE CANCER CARCINOGENESIS Taduru L. Sreenath, Shiela S. Macalindong, Natallia Mikhalkevich, Shashwat Sharad, Parameet Kumar, Denise Young, Rishita Gupta, Shilpa Katta, Ahmed Mohamed, Shyh-Han Tan, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Charles J. Bieberich, Peter Nelson, David G. McLeod, Valeri Vasioukhin, and Shiv Srivastava Taduru L. SreenathTaduru L. Sreenath More articles by this author , Shiela S. MacalindongShiela S. Macalindong More articles by this author , Natallia MikhalkevichNatallia Mikhalkevich More articles by this author , Shashwat SharadShashwat Sharad More articles by this author , Parameet KumarParameet Kumar More articles by this author , Denise YoungDenise Young More articles by this author , Rishita GuptaRishita Gupta More articles by this author , Shilpa KattaShilpa Katta More articles by this author , Ahmed MohamedAhmed Mohamed 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 A. SesterhennIsabell A. Sesterhenn More articles by this author , Charles J. BieberichCharles J. Bieberich More articles by this author , Peter NelsonPeter Nelson More articles by this author , David G. McLeodDavid G. McLeod More articles by this author , Valeri VasioukhinValeri Vasioukhin More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2234AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES High levels of the ERG expression due to gene fusions (predominantly TMPRSS2-ERG) is frequently detected in prostate cancer (CaP) in Western countries. Better understanding of the roles of the ERG oncogenic functions in CaP initiation and/or progression will enhance its utility as the therapeutic target. Transgenic mice generated to understand ERG’s role in the development of prostate adenocarcinoma have shown focal proliferative and dysplastic PIN lesions and later developed adenocarcinoma in older mice. Mice with ERG and PTEN alterations exhibit more accelerated malignant progression in prostate. The present study was aimed towards understanding the biological functions of ERG in early stages oncogenic transformation of prostate epithelium. METHODS Morphological analyses of mouse prostate glands were analyzed by H&E staining and by electron microscopy. Luminal cell surface markers were analyzed by FACS analysis. Luminal cells were analyzed for their potential to proliferate and form spheres by prostate sphere formation assay. ER stress and UPR marker proteins were analyzed by Western blot analysis. Analysis of representative ER stress pathway in ERG-positive human prostate cancer was analyzed in CPDR-80 gene-chip array data set representing well- and poor differentiated tumors. RESULTS Histological examination of ERG-Tg mouse prostates revealed increased luminal cell death due to apoptosis. Subsequently, TEM analysis revealed significant morphological differences such as increased numbers of lysosomes, autophagosomes, concentric membrane bodies with ribosomes, and lipid droplets in the cytoplasm of transgenic secretory luminal epithelial cells. 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 induced cell death. Western blots of ERG-Tg mouse and LNCaP-ERG transfectants showed increased expression of ER stress sensors and UPR proteins. A strong positive correlation was also observed between ERG and P4HB/PDI, one of the ER stress response proteins in human prostate tumors. CONCLUSIONS Cumulative data from experimental models of ERG and human CaP suggests that ERG mediates ER stress resulting into the activation of UPR, cell death with eventual biological selection for cell survival. Taken together these data indicate a critical biological function for ERG in prostate cancer initiation. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1093 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Taduru L. Sreenath More articles by this author Shiela S. Macalindong More articles by this author Natallia Mikhalkevich More articles by this author Shashwat Sharad More articles by this author Parameet Kumar More articles by this author Denise Young More articles by this author Rishita Gupta More articles by this author Shilpa Katta More articles by this author Ahmed Mohamed 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 A. Sesterhenn More articles by this author Charles J. Bieberich More articles by this author Peter Nelson More articles by this author David G. McLeod More articles by this author Valeri Vasioukhin More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...