Dataset Information

Genome-wide RNA-sequencing (RNA-seq) of benign and malignant prostate cell lines without and with androgen (R1881) stimulation.

ABSTRACT: RNA-seq data were obtained from hTERT immortalized human prostate transit amplifying EP156T cells (+/- 10 nM R1881 for 48 hrs), progeny tumorigenic EPT3-M1 cells recovered from mouse metastatic tumor (+/- 10 nM R1881 for 48 hrs) and the prostate cancer cell lines LNCaP (+/- 10 nM R1881 for 48 hrs), VCaP (+/- 1 nM R1881 for 24 hrs) and 22Rv1 (+/- 1 nM R1881 for 24 hrs) (obtained from the American Type Culture Collection). All cells were either stimulated or not stimulated with the synthetic androgen R1881 (1 or 10 nM for 24 or 48 hrs) prior to lysis (Qiagen miRNeasy minikit lysis buffer) and total RNA purification and DNase treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71797 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA292095

REPOSITORIES: GEO

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Project description:Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand binding domain (LBD)-binding antagonists, are inactivated by common resistance -mechanisms. It is important to develop next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. UT-34 inhibits the wild-type and LBD mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist, enzalutamide, and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug. MR49F cells (n=3-4/group) were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S) UT-34 is a selective androgen receptor degrader that degrades and antagonizes the AR. UT-34 binds to the AF-1 domain of the AR and degrades the AR through ubiquitin proteasome pathways. The transcriptome study was performed to evaluate the ability of UT-34 to antagonize the enzalutamide-resistant AR function.

Dataset Information

Genome-wide RNA-sequencing (RNA-seq) of benign and malignant prostate cell lines without and with androgen (R1881) stimulation.

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