1449 P38 MAP KINASE ASSOCIATES WITH ANDROGEN RECEPTOR (AR) AND MODULATES AR SIGNALING IN PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 20111449 P38 MAP KINASE ASSOCIATES WITH ANDROGEN RECEPTOR (AR) AND MODULATES AR SIGNALING IN PROSTATE CANCER CELLS Sweaty Koul, Douglas Lim, Fernando J. Kim, Randall B. Meacham, and Hari Koul Sweaty KoulSweaty Koul Aurora, CO More articles by this author , Douglas LimDouglas Lim Aurora, CO More articles by this author , Fernando J. KimFernando J. Kim Aurora, CO More articles by this author , Randall B. MeachamRandall B. Meacham Aurora, CO More articles by this author , and Hari KoulHari Koul Aurora, CO More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1362AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES p38 MAP kinase signal transduction pathway is activated by various forms of cellular stress. While, in many tissues activation of p38 MAP kinase is associated with apoptosis, in some tissues p38 activation is critical for survival. Indeed activation of p38 MAP kinase pathway has been shown in several tumor types, but the role of p38 MAP kinase to prostate cancer biology and castrate resistant PCa has not been clearly delineated. Present studies aimed at understanding the role of p38 MAP kinase pathway in prostate cancer with special emphasis on Androgen Receptor signaling. METHODS LNCaP cells, were grown at high densities in RPMI medium supplemented with 10% Fetal Calf Serum, 1mM Sodium Pyruvate and antibiotics and maintained at 37 °C in 5% CO2 incubator. Western blot analysis was used to measure amount and activity of p38 MAP kinase, and Luciferase reporter assays were used to determine the activity of Androgen Receptor proteins. Immuno precipitation and Western blot combination was used to probe interaction of AR with p38 MAP kinase. Chemical inhibitor, dominant negative expression and shRNA to p38 MAP kinase was used to regulate p38 MAP kinase activity and levels. Well established protocols in the lab probed the effects of these treatments on cell viability, invasion, clonogenic activity and invasive behavior of the cells. RESULTS We observed that suppression of p38 MAP kinase activity by a variety of approaches decreased viability and growth of LNCaP cells in culture. We also observed that androgen depletion was associated with increased activation of p38 MAP kinase activity and inhibition of p38 MAP kinase sensitized these cells to androgen depletion. Our results show that activation of p38 MAP kinase during androgen depletion was associated with androgen independent AR activation. Results of IP experiments show for the first time that AR co-localized withp38 MAP kinase and finally and most surprisingly, stable suppression of p38 MAP kinase using Lentiviral shRNA approach resulted in complete loss of AR activity and AR protein levels. CONCLUSIONS These data show, for the first time, critical requirement for p38 MAP kinase in androgen receptor signaling in prostate cancer cells; and show for the first time, in any cell type, the regulation of AR expression by p38 MAP kinase signaling pathway. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e581 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sweaty Koul Aurora, CO More articles by this author Douglas Lim Aurora, CO More articles by this author Fernando J. Kim Aurora, CO More articles by this author Randall B. Meacham Aurora, CO More articles by this author Hari Koul Aurora, CO More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...