1327 NF-κB2/P52 INDUCES RESISTANCE TO ENZALUTAMIDE POSSIBLY BY UPREGULATION OF AR-V7

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (VI)1 Apr 20131327 NF-κB2/P52 INDUCES RESISTANCE TO ENZALUTAMIDE POSSIBLY BY UPREGULATION OF AR-V7 Nagalakshmi Nadiminty, Ramakumar Tummala, Wei Lou, Joy C. Yang, Christopher P. Evans, and Allen C. Gao Nagalakshmi NadimintyNagalakshmi Nadiminty Sacramento, CA More articles by this author , Ramakumar TummalaRamakumar Tummala Sacramento, CA More articles by this author , Wei LouWei Lou Sacramento, CA More articles by this author , Joy C. YangJoy C. Yang Sacramento, CA More articles by this author , Christopher P. EvansChristopher P. Evans Sacramento, CA More articles by this author , and Allen C. GaoAllen C. Gao Sacramento, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2681AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Despite initial response of prostate cancer (CaP) to androgen deprivation, clinical observations suggest that castration-resistant prostate cancer (CRPC) develops resistance to the recently approved anti-androgen, enzalutamide. There is an urgent need to identify pathways that perpetuate disease progression during AR blockade. Identification of these resistance pathways will help design co-targeting strategies to improve the magnitude and duration of benefit of enzalutamide in CRPC. Our previous studies have demonstrated that NF-κB2/p52 plays an important role in the aberrant activation of AR in CaP. In this study we tested whether NF-κB2/p52 mediates resistance to enzalutamide in CaP cells. METHODS Cell growth was analyzed in LNCaP cells stably expressing p52 (LN-p52) and control cells (LN-neo) treated with enzalutamide. C4-2B cells were transfected with shRNA against p52 and cell growth was monitored. Expression levels of p52 in CaP cells grown chronically in enzalutamide were analyzed by Western blotting. Expression of AR variant AR-V7 was examined in LN-p52 and LN-neo cells by qRT-PCR and Western blotting. Expression of p52 was downregulated in VCaP and 22Rv1 cells by shRNA followed by treatment with enzalutamide and cell growth was monitored. Expression of AR-V7 was examined by qRT-PCR and Western blotting in VCaP and 22Rv1 cells transfected with shRNA against p52. RESULTS LN-p52 cells exhibited significantly better growth rates compared to LN-neo cells in the presence of enzalutamide, indicating that NF-κB2/p52 may enhance the survival of CaP cells treated with enzalutamide. Downregulation of p52 in castration resistant C4-2B cells reduced cell survival when treated with enzalutamide, suggesting that p52 may mediate resistance to enzalutamide. Expression levels of p52 were enhanced in enzalutamide resistant C4-2B cells generated by chronic treatment with enzalutamide, indicating that increased expression of p52 may facilitate the development of resistance to enzalutamide. We also found that LN-p52 cells exhibited higher levels of AR-V7 compared to LN-neo cells. Downregulation of p52 in VCaP and 22Rv1 cells (expressing endogenous levels of AR variants such as AR-V7) decreased the expression of AR-V7, demonstrating that p52 may regulate alternative splicing of AR mRNA. CONCLUSIONS Our findings demonstrate an important role for NF-κB2/p52 in inducing resistance to enzalutamide in CaP cells. Our results also suggest that NF-κB2/p52 may regulate resistance to enzalutamide via upregulation of AR-V7. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e542 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nagalakshmi Nadiminty Sacramento, CA More articles by this author Ramakumar Tummala Sacramento, CA More articles by this author Wei Lou Sacramento, CA More articles by this author Joy C. Yang Sacramento, CA More articles by this author Christopher P. Evans Sacramento, CA More articles by this author Allen C. Gao Sacramento, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...