1286 ABERRANT ACTIVATION OF THE ANDROGEN RECEPTOR BY NF-KAPPAB2/P52 (2010)

You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101286 ABERRANT ACTIVATION OF THE ANDROGEN RECEPTOR BY NF-KAPPAB2/P52 Nagalakshmi Nadiminty, Wei Lou, and Allen Gao Nagalakshmi NadimintyNagalakshmi Nadiminty More articles by this author , Wei LouWei Lou More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.870AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Castration-resistant progression of prostate cancer occurs in >80% of patients after failure of hormonal therapy but the underlying mechanisms are incompletely understood. Emerging evidence implies that ligand-independent activation of the androgen receptor (AR) is of critical importance during this process. Our previous studies show that the levels of NF-κB2/p52 are elevated in prostate cancer cells and that active NF-κB2/p52 promotes prostate cancer cell growth in vitro and in vivo. In this study, we examined the role of NF-κB2/p52 in the aberrant activation of the AR during castration resistant progression, in contrast to the interaction between the AR and RelA/p65. METHODS The effects of NF-κB2/p52 on cell survival, growth and androgen responsiveness were examined in prostate cancer cells. Modulation of LNCaP tumor growth by p52 was examined in intact and castrated male nude mice. Effect of p52 or p65 on AR activation was examined using luciferase assays, EMSA, ChIP assays and ELISA. RESULTS Expression of NF-kB2/p52 enhanced androgen-sensitive LNCaP human CaP cell growth and clonogenic ability in androgen-deprived conditions in vitro. LNCaP cells expressing p52 exhibited protection from apoptotic cell death and cell cycle arrest induced by androgen-deprivation. Adenoviral mediated p52 expression in LNCaP cells induced tumor growth in castrated male nude mice. NF-kB/p52 induced the activation of the AR resulting in increased transactivation of AR-responsive genes such as PSA and NKX3.1 in a ligand-independent manner. NF-kB2/p52 enhanced nuclear translocation and transactivation of AR by interacting with its N-terminal domain and enhanced the recruitment of co-activators like p300 to the promoters of AR-dependent genes. These results were confirmed in 3 different prostate cancer cell lines: LAPC-4 (wild type AR), LNCaP (mutant AR) and C4-2 (androgen-insensitive). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. In contrast, we observed that p65 exhibited transcriptional repression of the AR, and did not induce expression of AR-responsive genes, PSA and NKX3.1. CONCLUSIONS These findings demonstrate that overexpression of NF-kB2/p52 induces castration-resistant growth and aberrant activation of the AR in LNCaP cells. NF-kB2/p52 may promote castration resistant progression by activating the AR under conditions of androgen deprivation. Sacramento, CA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e498 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nagalakshmi Nadiminty More articles by this author Wei Lou More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...