1459 RATIONALLY DESIGNED LXXLL PEPTIDOMIMETIC BLOCKS NON-ANDROGENIC ACTIVATION OF THE ANDROGEN RECEPTOR IN PROSTATE TUMOR

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 20111459 RATIONALLY DESIGNED LXXLL PEPTIDOMIMETIC BLOCKS NON-ANDROGENIC ACTIVATION OF THE ANDROGEN RECEPTOR IN PROSTATE TUMOR Lin Yang, Preethi Ravindranath, Jung-Mo Ahn, and Ganesh Raj Lin YangLin Yang Dallas, TX More articles by this author , Preethi RavindranathPreethi Ravindranath Dallas, TX More articles by this author , Jung-Mo AhnJung-Mo Ahn Dallas, TX More articles by this author , and Ganesh RajGanesh Raj Dallas, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1372AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In our previous study, we have shown that Estrogen Receptor beta (ERβ), PELP1 and Androgen Receptor (AR) can form a heterotrimeric protein complex in prostate cancer (PCa) cells. This complex plays a central role in the non-androgenic activation of AR in PCa. We had also previously rationally designed an LXXLL peptidomimetic, D2, block the formation of the heterotrimeric complex between AR, PELP1 and ERβ. In this study, we examined if this peptidomimetic D2 could inhibit the non-androgenic activation of AR in PCa cells. METHODS PCa cells were pretreated with either the active peptidomimetic D2, control peptidomimetic D1, or vehicle (DMSO) for 2 hours, and then treated with 10 nM of estradiol for 24 hours. PCa cells were harvested and immunoprecipitation was done to check if D2 blocked the formation of the complex; MTT assay, luciferase assay and Western Blotting were done to check if D2 blocked estrogen-induced AR activation; PELP1 was then transfected into C4-2 cells to check if overexpression of PELP1 could rescue the D2 blocked estrogen-induced AR activation. RESULTS D2 can block the formation of ERβ, PELP1 and AR complex in PCa cells. Upon treatment with E2, this complex is induced, but pretreatment with D2 prevents induction of the heterotrimeric protein complex. D2 but not D1 can block estradiol induced PCa cell proliferation. D2 can downregulate estradiol induced PSA gene expression, and transcription from androgen responsive elements (ARE). Finally, D2 can block Estradiol-induced AR nuclear translocation. Overexpression of PELP1 in C4-2 cells can rescue the PCa cell proliferation, PSA gene expression, ARE luciferase activity and AR nuclear translocation from the suppressive effects of D2. CONCLUSIONS These data suggest that ERβ, PELP1 and AR form a heterotrimeric protein complex. The rationally signed LXXLL analogue D2 blocked the formation of this complex. Blockade of this protein complex with D2 blocks the non-androgenic activation of PCa cells, including PCa cell proliferation, ARE-driven gene expression and AR nuclear translocation. Over-expression of PELP1 in PCa cells can rescue the cells from the effect of D2, by restoring a functional concentration of PELP1 above the direct competitive inhibition of D2. These data indicate that the rationally designed peptidomimetic D2 can block both the androgenic and non-androgenic activation of AR in PCa cells. This feature makes the peptidomimetic D2 very attractive for further development. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e585 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lin Yang Dallas, TX More articles by this author Preethi Ravindranath Dallas, TX More articles by this author Jung-Mo Ahn Dallas, TX More articles by this author Ganesh Raj Dallas, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...