RNA-Seq analysis of prostate cancer cell line LNCaP treated with vehicle, androgen, androgen and IMTPPE, androgen and JJ-(+)-450, androgen and JJ-(-)450, androgen and enzalutamide
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PROVIDER: PRJNA474819 | ENA |
REPOSITORIES: ENA
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Project description:RNA-Seq analysis of prostate cancer cell line LNCaP treated with vehicle (C), androgen (R), androgen and IMTPPE (R + IMTPPE), androgen and JJ-(+)-450 (androgen + (-)450), androgen and JJ-(-)450 (androgen + (-)450), androgen and enzalutamide (androgen +Enz). To evaluate if our compounds can inhibit AR function specifically and completely, LNCaP mRNA profiles of cells treated with IMTPPE, (+)-JJ-450 and (-)-JJ-450, comparing to enzalutamide. RNA isolation was performed using RNeasy Mini kit (Qiagen), RNA Sequencing was carried out by Genomics Research Core of University of Pittsburgh using Illumina NextSeq 500 system. The sequence reads that passed FASTQC were analyzed at the transcript level. Each sample was mapped to the Human Ensembl reference genome GRCh38. We definied different expression genes with a fold change ≥2.0 and FDR <0.05. Both (-)-JJ-450 and enzalutamide are very specific to AR, with 56 and 186 DE genes comparing to control samples respectively. IMTPPE and (+)-JJ-450 can inhibit most of the androgen responsive genes, but also some other genes were affected. (-)-JJ-450 is a novel compound inhibts AR function specifically and completely, and it is a potential lead compound for the treatment of CRPC, including those resistant to enzalutamide.
2019-06-06 | GSE115395 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression. LNCaP cells were grown in RPMI 1640 supplemented with 5% hormone depleted FBS and treated with vehicle (control sample) , DHT (100 nM), enzalutamide (1 or 10 M-BM-5M) or DHT (100 nM) plus enzalutamide (1 or 10 M-BM-5M)for 16 hours for RNA extraction and hybridization. Each condition was done in triplicate.
2013-04-01 | E-GEOD-44905 | biostudies-arrayexpress
Project description:Transriptome analysis of LNCaP/AR cell line after concomittant treatment with androgen with bicalutamide and enzalutamide
2015-10-01 | GSE62474 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.
2016-06-10 | GSE69896 | GEO
Project description:The goal of this study was to determine how androgen receptor inhibition alters transcriptional programs in prostate cancer cells. LNCaP prostate cancer cells were grown in 10% charcoal-stripped serum (CSS) supplemented with 0.5 nanomolar dihydrotestosterone (DHT), in CSS without DHT modeling castration, with CSS + DHT but in the presence of 10 micromolar enzalutamide, or in CSS without DHT (castrated) and in the presence of enzalutamide for 72 hours. Analysis shows that androgen receptor target genes are reduced with castration, enzalutamide or the combination of castration + enzalutamide.
2022-05-12 | GSE202755 | GEO
Project description: Not available
| S-EPMC7421602 | biostudies-literature
Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression.
2013-04-01 | GSE44905 | GEO
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.
2019-12-31 | GSE133119 | GEO
Project description:LNCaP prostate cancer cells were stimulated with the synthetic androgen R1881. RNA-sequencing was performed to identify changes induced by enzalutamide treatment on the transcriptome level.
2023-02-15 | GSE220097 | GEO