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Human prostate cancer cells (VCaP and AIVCaP): siAR alone (single siRNA) vs. siAR plus OPRK1 (combo-siRNA)

ABSTRACT: Through comparative genomics using PDX models of androgen-dependent (AD) and castration-resistant (CR) tumors, we identify opioid receptor kappa 1 (OPRK1) as being associated with castration-resistance. Loss of OPRK1 function delays castration-resistance and inhibits castration-resistant growth of prostate cancer cells in culture and in vivo, suggesting OPRK1 as a therapeutic target. To gain insight with regard to biological function of OPRK1 under androgen-depleted condition, we set up two distinct comparisons using VCaP and AIVCaP cells. AIVCaP is an androgen-independent subline of VCaP which we established. VCaP or AIVCaP were treated with siRNA for AR plus siRNA for OPRK1 (combo-siRNA) or siRNA for AR alone (single siRNA) (n = 4 each), and then expression profile gained from microarray analysis of the respective cell line treated with combo-siRNA was compared with that of cells treated with single siRNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194248 | GEO | 2022/04/03

REPOSITORIES: GEO

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Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.