Prostate Cell Specific Regulation of Androgen Receptor Phosphorylation In Vivo

2006 ◽  
Author(s):  
Samir Taneja ◽  
Susan Logan ◽  
Brian Dynlacht ◽  
Michael Garabedian ◽  
Derick Mitchell
Keyword(s):  
Androgen Receptor ◽  
Receptor Phosphorylation ◽  
Prostate Cell ◽  
Specific Regulation

scholarly journals Identification of androgen receptor phosphorylation in the primate ovary in vivo

Reproduction ◽  
2010 ◽  
Vol 140 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Iain J McEwan ◽  
Dagmara McGuinness ◽  
Colin W Hay ◽  
Robert P Millar ◽  
Philippa T K Saunders ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Androgen Receptor ◽  
Granulosa Cells ◽  
Gnrh Antagonist ◽  
Follicular Phase ◽  
Surface Epithelium ◽  
Control Group ◽  
Target Tissue ◽  
Receptor Phosphorylation

The androgen receptor (AR) is a member of the nuclear receptor superfamily, and is important for both male and female reproductive health. The receptor is a target for a number of post-translational modifications including phosphorylation, which has been intensively studied in vitro. However, little is known about the phosphorylation status of the receptor in target tissues in vivo. The common marmoset is a useful model for studying human reproductive functions, and comparison of the AR primary sequence from this primate shows high conservation of serines known to be phosphorylated in the human receptor and corresponding flanking amino acids. We have used a panel of phosphospecific antibodies to study AR phosphorylation in the marmoset ovary throughout the follicular phase and after treatment with GNRH antagonist or testosterone propionate. In normal follicular phase ovaries, total AR (both phosphorylated and non-phosphorylated forms) immunopositive staining was observed in several cell types including granulosa cells of developing follicles, theca cells and endothelial cells lining blood vessels. Receptor phosphorylation at serines 81, 308, and 650 was detected primarily in the granulosa cells of developing follicles, surface epithelium, and vessel endothelial cells. Testosterone treatment lead to a modest increase in AR staining in all stages of follicle studied, while GNRH antagonist had no effect. Neither treatment significantly altered the pattern of phosphorylation compared to the control group. These results demonstrate that phosphorylation of the AR occurs, at a subset of serine residues, in a reproductive target tissue in vivo, which appears refractory to hormonal manipulations.

Characterisation of CCS1477: A novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11590-11590 ◽  
Author(s):  
Neil Pegg ◽  
Nigel Brooks ◽  
Jenny Worthington ◽  
Barbara Young ◽  
Amy Prosser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Prostate Cell ◽  
Molecule Inhibitor ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
And Function ◽  
Prostate Cell Lines

11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.

scholarly journals Zimp7 and Zimp10, two novel PIAS-like proteins, function as androgen receptor coregulators

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04017 ◽  
Author(s):  
Jason Beliakoff ◽  
Zijie Sun
Keyword(s):  
Androgen Receptor ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Prostate Cell ◽  
Knockout Mouse Model ◽  
Growth And Survival ◽  
Functional Roles ◽  
Malignant Prostate

The androgen receptor (AR) plays a critical role in male sexual development and in normal and malignant prostate cell growth and survival. It has been shown that AR transcriptional activation is regulated through interactions with a variety of transcriptional co-regulators. The Protein Inhibitors of Activated STATs (PIAS) are transcriptional co-regulators, and have been shown to modulate AR-mediated transcription. In this brief, we summarize our recent studies on two novel PIAS-like proteins, Zimp7 and Zimp10. Particularly, we address the functional interactions between the AR and these two proteins, and potential mechanisms by which they regulate AR mediated transcription. In addition, we explore potential roles of Zimp10 in transcriptional regulation in vivo using a recent Zimp10 knockout mouse model. Taken together, our findings thus far suggest that Zimp7 and Zimp10 are functionally non-redundant and share unique characteristics that have not been described for the PIAS family. Further investigation into the functional roles of these two PIAS-like proteins may help to better understand prostate cancer progression, and yield possible new targets for therapeutic intervention.

Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor

2010 ◽  
Vol 433 (1) ◽  
pp. 235-244 ◽  
Author(s):  
Kyung-Chul Choi ◽  
SiYong Park ◽  
Beom Jin Lim ◽  
Ah-Reum Sung ◽  
Yoo-Hyun Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cancer Cell ◽  
Histone Acetyltransferase ◽  
Prostate Cancer Cell ◽  
Cancer Cell Growth ◽  
Prostate Cell

Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro-B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth.

scholarly journals Interrogation of gender disparity uncovers androgen receptor as the transcriptional activator for oncogenic miR-125b in gastric cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ben Liu ◽  
Meng Zhou ◽  
Xiangchun Li ◽  
Xining Zhang ◽  
Qinghua Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gender Bias ◽  
Gender Disparity ◽  
Gene Set Enrichment Analysis ◽  
Cancer Type ◽  
Female Patients

AbstractThere is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

scholarly journals Recruitment of β-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells

2004 ◽  
Vol 18 (10) ◽  
pp. 2388-2401 ◽  
Author(s):  
David Masiello ◽  
Shao-Yong Chen ◽  
Youyuan Xu ◽  
Manon C. Verhoeven ◽  
Eunis Choi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Nuclear Receptor ◽  
Specific Antigen ◽  
Prostate Cancer Cells ◽  
Prostate Cell ◽  
Nuclear Receptor Corepressor ◽  
Prostate Cancers

Abstract Prostate cancers respond to treatments that suppress androgen receptor (AR) function, with bicalutamide, flutamide, and cyproterone acetate (CPA) being AR antagonists in clinical use. As CPA has substantial agonist activity, it was examined to identify AR coactivator/corepressor interactions that may mediate androgen-stimulated prostate cancer growth. The CPA-liganded AR was coactivated by steroid receptor coactivator-1 (SRC-1) but did not mediate N-C terminal interactions or recruit β-catenin, indicating a nonagonist conformation. Nonetheless, CPA did not enhance AR interaction with nuclear receptor corepressor, whereas the AR antagonist RU486 (mifepristone) strongly stimulated AR-nuclear receptor corepressor binding. The role of coactivators was further assessed with a T877A AR mutation, found in LNCaP prostate cancer cells, which converts hydroxyflutamide (HF, the active flutamide metabolite) into an agonist that stimulates LNCaP cell growth. The HF and CPA-liganded T877A ARs were coactivated by SRC-1, but only the HF-liganded T877A AR was coactivated by β-catenin. L-39, a novel AR antagonist that transcriptionally activates the T877A AR, but still inhibits LNCaP growth, similarly mediated recruitment of SRC-1 and not β-catenin. In contrast, β-catenin coactivated a bicalutamide-responsive mutant AR (W741C) isolated from a bicalutamide-stimulated LNCaP subline, further implicating β-catenin recruitment in AR-stimulated growth. Androgen-stimulated prostate-specific antigen gene expression in LNCaP cells could be modulated by β-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, but not CPA. These results indicate that interactions between AR and β-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of β-catenin remain to be identified.

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