973 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE IS A THERAPEUTIC TARGET FOR BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2010973 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE IS A THERAPEUTIC TARGET FOR BLADDER CANCER Monica Liebert, Stephanie Tseng-Rogenski, Lakshmi Kunju, Alon Weizer, David Wood, and Cheryl Lee Monica LiebertMonica Liebert More articles by this author , Stephanie Tseng-RogenskiStephanie Tseng-Rogenski More articles by this author , Lakshmi KunjuLakshmi Kunju More articles by this author , Alon WeizerAlon Weizer More articles by this author , David WoodDavid Wood More articles by this author , and Cheryl LeeCheryl Lee More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1920AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 15-hydroxyprostaglandin dehydrogenase (PGDH) is an enzyme responsible for inactivation of powerful tumor promoting molecule prostaglandin E2 (PGE2). Recent studies have shown that PGDH is a tumor suppressor in colon, lung, gastric and breast cancers. The objective of this study was to determine if restoration of PGDH expression provides a therapeutic effect for bladder cancer. METHODS PGDH immunostaining was performed in 128 paraffin-embedded tissue samples. PGDH expression in 8 human bladder cancer cell lines was determined using Western blotting. Restoration of PGDH expression was accomplished using a ″Tet On″ lentiviral system (Invitrogen). Cells were first infected with a lentivirus carrying the tetracycline repressor gene. After selection with Blasticidin, infected cells were treated with a second lentivirus containing the genetic sequence for PGDH or a control reverse sequence (HDGP). Infected cells were selected by treatment in culture with Blasticidin and Zeocin. PGDH expression was induced in cells by treatment with tetracycline. Statistics were evaluated using SigmaStat v3.5. RESULTS By immunostaining, 18/19 normal urothelial samples showed strong staining (2-3+ staining, 95%). Staining was reduced in many lower stage (Ta) samples (only 22/37 showed strong staining, 59%) and lost in most invasive bladder cancer samples (6/72 samples strongly positive, 8%; p<.0001, χ2). Western blotting confirmed PGDH expression in only 2/8 bladder cancer cell lines. Restoration of PGDH expression in the PGDH-negative UM-UC3 human bladder cancer cell line slowed cell growth, and eventually the cells died with fragmentation of the cell nuclei. Previous studies assume that PGDH tumor suppressor activity is due to lower local PGE2 levels. However, attempted ″rescue″ of PGDH-expressing UM-UC-3 cells with exogenous PGE2 treatment failed, suggesting that restoration of PGDH expression has additional novel anti-tumor effects. CONCLUSIONS PGDH expression is lost early in bladder cancer progression. Restoration of PGDH expression in the UM-UC3 cell line resulted in cell death. This effect appears to be independent of the reduced level of PGE2 in the environment, a previously unappreciated and novel activity. These data indicate that PGDH restoration has therapeutic potential for bladder cancer. Ann Arbor, MI© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e378 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Monica Liebert More articles by this author Stephanie Tseng-Rogenski More articles by this author Lakshmi Kunju More articles by this author Alon Weizer More articles by this author David Wood More articles by this author Cheryl Lee More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...