MP61-10 SILENCING OF PMEPA1 IS ASSOCIATED WITH ACTIVATION OF AR SIGNALING IN HUMAN PROSTATE CANCER AND CASTRATION RESISTANT TUMOR GROWTH IN NUDE MOUSE

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2015MP61-10 SILENCING OF PMEPA1 IS ASSOCIATED WITH ACTIVATION OF AR SIGNALING IN HUMAN PROSTATE CANCER AND CASTRATION RESISTANT TUMOR GROWTH IN NUDE MOUSE Hua Li, Elizabeth Umeda, Yingjie Song, Denise Young, Lakshmi Ravindranath, Ahmed A. Mohamed, Yongmei Chen, Shashwat Sharad, Gyorgy Petrovics, David G. McLeod, Isabell Sesterhenn, Taduru Sreenath, Albert Dobi, and Shiv Srivastava Hua LiHua Li More articles by this author , Elizabeth UmedaElizabeth Umeda More articles by this author , Yingjie SongYingjie Song More articles by this author , Denise YoungDenise Young More articles by this author , Lakshmi RavindranathLakshmi Ravindranath More articles by this author , Ahmed A. MohamedAhmed A. Mohamed More articles by this author , Yongmei ChenYongmei Chen More articles by this author , Shashwat SharadShashwat Sharad More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , David G. McLeodDavid G. McLeod More articles by this author , Isabell SesterhennIsabell Sesterhenn More articles by this author , Taduru SreenathTaduru Sreenath More articles by this author , Albert DobiAlbert Dobi More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2191AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The androgen receptor (AR) dysfunctions contribute to prostate cancer (CaP) development and progression. Earlier we defined the regulation of AR protein levels by a negative feed-back loop between AR and the androgen regulated PMEPA1, a NEDD4 E3 ubiquitin ligase binding protein. Our data also revealed decreased or absent PMEPA1 transcripts in 65% prostate tumors. This study focuses on the relationship of PMEPA1 protein with AR and its transcriptional targets (PSA) in human CaP, as well as the impact of PMEPA1 silencing on growth of PMEPA1-shRNA LNCaP cells derived tumors in naïve and castrated nude mice. METHODS Ten weeks old athymic Ncr-nu/nu mice were evaluated for the growth of tumor xenografts derived from PMPEA1-shRNA LNCaP (N=20) and control-shRNA LNCaP cells (N=20). Each mouse received 4×106 cells by subcutaneous injection to right flank side. The mice with tumors were castrated at 9th week post-injection. The tumor sizes were monitored twice per week until 16th week post-injection. The xenograft tissues were assayed by immunohistochemical (IHC) staining for PMEPA1, AR and PSA protein levels. The AR, PMEPA1 and PSA expressions in whole mount human prostate specimens were evaluated by IHC staining and QRT-PCR. RESULTS The PMEPA1 shRNA-LNCaP and control shRNA-LNCaP cells started to form subcutaneous tumors at 4 weeks after injections. However, the growth rate of PMEPA1 shRNA-LNCaP derived tumors was significantly faster than control derived tumors (P<0.05). PMEPA1 shRNA-LNCaP tumors expressed higher levels of AR and PSA proteins as assessed by IHC. At 7 weeks after castration the tumor sizes increased by 69% in the control group in contrast to 304% in the PMEPA1-shRNA harboring xenografts (P<0.05). In human CaP, decreased PMEPA1 mRNA expression significantly correlated with increased levels of AR transcription target PSA, as a surrogate for elevated AR. Focally increased PSA and AR protein levels were detected in a subset of low PMEPA1 expressing tumors. CONCLUSIONS PMEPA1 silencing in CaP cells leads to gain of AR, increased tumor growth with potential to induce resistance to AR inhibition targeted therapy. Decreased PMEPA1 in human CaP correlated with increased AR activity. Thus, monitoring PMEPA1 expression in CaP cells offers new opportunities in therapeutic stratification of CaP. Further, restoring PMEPA1 in CaP cells provide a new strategy for AR degradation focused therapy. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e750 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hua Li More articles by this author Elizabeth Umeda More articles by this author Yingjie Song More articles by this author Denise Young More articles by this author Lakshmi Ravindranath More articles by this author Ahmed A. Mohamed More articles by this author Yongmei Chen More articles by this author Shashwat Sharad More articles by this author Gyorgy Petrovics More articles by this author David G. McLeod More articles by this author Isabell Sesterhenn More articles by this author Taduru Sreenath More articles by this author Albert Dobi More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...