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• W2100094436 abstract "You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2015MP46-03 NF-KAPPAB2/P52:C-MYC:HNRNPA1 REGULATORY PATHWAY CONTROLS EXPRESSION OF ANDROGEN RECEPTOR SPLICE VARIANTS AND ENZALUTAMIDE SENSITIVITY IN PROSTATE CANCER Nagalakshmi Nadiminty, Ramakumar Tummala, Chengfei Liu, Wei Lou, Christopher Evans, and Allen Gao Nagalakshmi NadimintyNagalakshmi Nadiminty More articles by this author , Ramakumar TummalaRamakumar Tummala More articles by this author , Chengfei LiuChengfei Liu More articles by this author , Wei LouWei Lou More articles by this author , Christopher EvansChristopher Evans More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1566AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation anti-androgens such as enzalutamide. In this study we tested whether increased expression of NF-kappaB2/p52 and the NF-kappaB2/p52:c-Myc:hnRNPA1 regulatory pathway controls expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer. METHODS Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, ELISA and Western blotting were performed to detect expression levels of PSA, p52, c-myc, HnRNPA1/2, and AR. Expression of p52, c-myc, HnRNPA1/2, AR-V7 was downregulated using siRNA. RESULTS C4-2B and CWR22Rv1 cells chronically treated with Enzalutamide were found to express higher levels of NF-kappaB2/p52. Downregulation of NF-kappaB2/p52 in CWR22Rv1 cells chronically treated with Enzalutamide rendered them more sensitive to cell growth inhibition by Enzalutamide. Analysis of the expression levels of AR splice variants by qRT-PCR and Western blotting revealed that LNCaP cells expressing p52 exhibit higher expression of AR splice variants. We demonstrate that the splicing factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in the generation of AR splice variants such as AR-V7. HnRNPA1 is overexpressed in prostate tumors compared to benign prostates and its expression is regulated by NF-kappaB2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-kappaB2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and of AR-V7 are positively correlated with each other in PCa. The regulatory circuit involving NF-kappaB2/p52, c-Myc and hnRNPA1 plays a central role in the generation of AR splice variants. Downregulation of hnRNPA1 and consequently of AR-V7 resensitizes enzalutamide-resistant cells to enzalutamide, indicating that enhanced expression of hnRNPA1 may confer resistance to AR-targeted therapies by promoting the generation of splice variants. CONCLUSIONS These findings demonstrate that the NF-kappaB2/p52:c-Myc:hnRNPA1 regulatory pathway controls expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer, and may provide a rationale for co-targeting these pathways to achieve better efficacy through AR blockade. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e544 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nagalakshmi Nadiminty More articles by this author Ramakumar Tummala More articles by this author Chengfei Liu More articles by this author Wei Lou More articles by this author Christopher Evans More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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• W2100094436 title "MP46-03 NF-KAPPAB2/P52:C-MYC:HNRNPA1 REGULATORY PATHWAY CONTROLS EXPRESSION OF ANDROGEN RECEPTOR SPLICE VARIANTS AND ENZALUTAMIDE SENSITIVITY IN PROSTATE CANCER" @default.
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