Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22914 | GEO | 2011/08/05
SECONDARY ACCESSION(S): PRJNA127969
REPOSITORIES: GEO
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Project description:Prostate epithelial cells depend on androgens for survival and function. In early prostate cancer, besides survival, androgens also regulated tumor growth, which is exploited by androgen ablation/ blockade therapies in metastatic disease. The aim of the present study was to characterize the role of the androgen receptor pathway in prostate cancer progression and to identify potential disease markers. Microarray analysis was used to establish the androgen-regulated gene expression profile, upon stimulation with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide, of the androgen-responsive PC346C cell line and its derivative castration-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A mutated AR) PC346C, PC346DCC, PC346Flu1 and PC346Flu2 were stimulated with 1 nM R1881, 1uM hydroxyflutamide or vehicle control, following a 4, 8 and 16h time-course. Each condition was performed in dye-swap, using biological duplicates. PC346DCC was only stimulated with R1881, not hydroxyflutamide.
2011-08-04 | E-GEOD-22914 | biostudies-arrayexpress
Project description:Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for invasive tumors. However, despite initial remission, the cancer will inevitably recur. The present study was set to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions Microarray technology was used to analyze differences in gene expression between androgen-responsive and hormone-refractory prostate cancer cell lines. As model system, we used the androgen-responsive PC346C cells and its castration-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. These sublines were derived from the parental PC346C by long-term androgen ablation (PC346DCC), supplemented with the antiandrogen hydroxyflutamide (PC346Flu1 and PC346Flu2). Previous studies revealed distinct AR modifications in all three castration-resistant sublines: AR overexpression (PC346Flu1), AR down-regulation (PC346DCC) and T877A AR mutation (PC346Flu2). Each of the hormone-refractory sublines were cultured in their respective selection medium (steroid-stripped medium for PC346DCC, supplemented with 1 mM OH-Flutamide for PC346Flu1 and Flu2) and hybridized on the microarrays, together with the parental androgen-responsive PC346C (cultured in complete medium supplemented with 0.1 nM R1881). To account for the biological variability and dye-preferential binding to oligonucleotides on the microarray, four replicate arrays were performed per cell line, using two independent cell passages in dye-swap.
2010-10-21 | E-GEOD-21596 | biostudies-arrayexpress
Project description:Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for invasive tumors. However, despite initial remission, the cancer will inevitably recur. The present study was set to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions Microarray technology was used to analyze differences in gene expression between androgen-responsive and hormone-refractory prostate cancer cell lines. As model system, we used the androgen-responsive PC346C cells and its castration-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. These sublines were derived from the parental PC346C by long-term androgen ablation (PC346DCC), supplemented with the antiandrogen hydroxyflutamide (PC346Flu1 and PC346Flu2). Previous studies revealed distinct AR modifications in all three castration-resistant sublines: AR overexpression (PC346Flu1), AR down-regulation (PC346DCC) and T877A AR mutation (PC346Flu2).
2010-10-21 | GSE21596 | GEO
Project description:Androgens are required for the development of normal prostate, and they are also linked to the development of prostate cancer. We used microarrays to understand the role of androgen in an androgen dependent, androgen receptor (AR) positive human metastatic cell line, LNCaP. LNCaP cells were grown in RPMI medium and they were subjected to stay in phenol-red free, RPMI with charcoal stripped serum for 48h. Synthetic androgen R1881 was added and the cells were allowed to grow for 48h. Control cells were given with corresponding amount of ethanol as vehicle which is used for the solubilization of R1881. Cells were harvested and RNA was isolated for microarray analysis.
2009-12-29 | E-GEOD-17044 | biostudies-arrayexpress
Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).
2016-06-30 | E-GEOD-61630 | biostudies-arrayexpress
Project description:Androgen receptor (AR) signaling is a major driver and therapy target in prostate cancer. Several inhibitors of AR function are approved for different stages of the disease and their impact on downstream gene transcription has been described. However, the ensuing effects of androgen and anti-androgens at the protein level are less well understood. Here, we focused on the AR inhibitor darolutamide which has recently been approved for non-metastatic castration-resistant prostate cancer. Here we determined the impact of darolutamide, a recently approved AR antagonist which significantly extends progression-free and overall survival in non-metastatic CRPC (31, 32), on the prostate cancer proteome. We first determined the direct binding between darolutamide and the AR in living prostate cancer cells in a label-free context using the cellular high throughput thermal shift assay (CETSA HT). We then generated comprehensive proteomic profiles of prostate cancer cells treated with androgen and darolutamide, and compared them with transcriptomic profiles. We found a generally high concordance between proteomic and transcriptomic data, both on the level of detected expressed genes and their protein products, as well as in terms of the corresponding biological programs. However there were cases where protein and gene expression levels were not regulated in parallel, suggesting an additional post-transcriptional regulation step controlling protein abundance to occur in several instances.
2023-02-17 | PXD036962 | Pride
Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer.1,2 LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]).1 In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers.3,4 Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription.5 Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signaling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers – pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term.
2016-06-30 | GSE61630 | GEO
Project description:Prostate cancer (PCa) is the most frequently diagnosed cancer in Canadian men and is the third cause of cancer mortality. PCa initiation and growth is driven by the androgen receptor (AR). AR is activated by androgens such as testosterone and controls prostatic cell proliferation and survival. We sought to characterize global AR signalling networks. We performed BioID proximity labeling proteomics in androgen-dependent LAPC4 cells to delineate AR protein interaction networks. We report the identification of 32 AR associated proteins in non-stimulated cells. Strikingly, the AR signalling network increased to 183 and 201 proteins, upon 24h or 72h androgenic stimulation, respectively. Among this group, we identified 215 proteins that were not previously reported as AR interactors. Interestingly, these AR associated proteins were previously reported to be involved in DNA metabolism, RNA processing and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, such as the Krüppel-like factor 4 (KLF4), which was specifically revealed in androgen-stimulated cells. We determined that KLF4 acts as a repressor of AR target genes transcription in PCa cells. Taken together, our data report the largest high-confidence proximity networks for AR in PCa cells.
2021-03-01 | PXD011974 | Pride
Project description:The androgen receptor (AR) mediates the action of androgens by binding to androgen-responsive elements (AREs) and subsequently regulating target genes involved in prostate carcinogenesis. The precise locations, true nature, and functional roles of AREs in human prostate cancer are still unknown. Here we redefine AREs by motif-resolution AR chromatin immunoprecipitation-exonuclease (ChIP-exo) assay in human prostate cancer cells and tumors. Surprisingly, we find that, in addition to canonical full-length AREs and half-site-like AREs, a significant portion of the four redefined ARE categories comprises non-canonical full-length AREs. The redefined AREs in enhanced AR binding regions in prostate tumors versus paired non-malignant adjacent tissues regulate a prostate cancer-relevant gene network not only centered on AR, but more interestingly, on novel AR target genes mTOR, BIRC5 and BCL2L1 involved in prostate cancer cell growth and survival. The precise redefinition of AREs has important implications for understanding how AR contributes to prostate carcinogenesis. FOXA1 ChIP-exo
2015-01-01 | E-GEOD-43678 | biostudies-arrayexpress
Project description:Aberrant androgen receptor (AR)-mediated transcription is a critical driver in progression of human prostate cancer. It's known that different doses of androgens can elicit differential transcriptional and proliferative responses in prostate-tumor cells. Here, we set out to examine the androgenic regulation of glycoprotein expression in the membrane fraction of prostate-tumor cells that could serve as mediators or markers of androgen-induced proliferative responses observed in prostate-tumor cells. A bioanalytical workflow involving lectin-affinity chromatography and label-free quantitative mass spectrometry was used to identify androgen-sensitive glycomembrane protein expression associated with androgen-mediated proliferation. This study would facilitate the identification of surface membrane proteins involved in androgen-mediated proliferation and provide potential therapeutic targets in the detection treatment of proliferation prostate-tumors.
2022-03-01 | PXD002913 | Pride