scholarly journals Mechanisms of androgen receptor repression in prostate cancer

2006 ◽  
Vol 34 (6) ◽  
pp. 1124-1127 ◽  
Author(s):  
S.M. Powell ◽  
G.N. Brooke ◽  
H.C. Whitaker ◽  
V. Reebye ◽  
S.C. Gamble ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Steroid Receptors ◽  
Significant Proportion ◽  
Repressor Proteins ◽  
Receptor Inhibition ◽  
Prostate Cancer Therapy ◽  
Androgen Receptor Activity ◽  
Prostate Cancers

Anti-androgens used in prostate cancer therapy inhibit AR (androgen receptor) activity via largely unknown mechanisms. Although initially successful in most cases, they eventually fail and the disease progresses. We need to elucidate how anti-androgens work to understand why they fail, and prolong their effects or design further therapies. Using a cellular model, we found different anti-androgens have diverse effects on subcellular localization of AR, revealing that they work via different mechanisms and suggesting that an informed sequential treatment regime may benefit patients. In the presence of the anti-androgens bicalutamide and hydroxyflutamide, a significant proportion of the AR is translocated to the nucleus but remains inactive. Receptor inhibition under these conditions is likely to involve recruitment of co-repressor proteins, which interact with antagonist-occupied receptor but inhibit receptor-dependent transcription. Which co-repressors are required in vivo for AR repression by anti-androgens is not clear, but one candidate is the Notch effector Hey1. This inhibits ligand-dependent activity of the AR but not other steroid receptors. Further, it is excluded from the nucleus in most human prostate cancers, suggesting that abnormal subcellular distribution of co-repressors may contribute to the aberrant hormonal responses observed in prostate cancer. A decrease in co-repressor function is one possible explanation for the development of anti-androgen-resistant prostate cancer, and this suggests that it may not occur at the gross level of protein expression.

scholarly journals Differential modulation of the androgen receptor for prostate cancer therapy depends on the DNA response element

2020 ◽  
Vol 48 (9) ◽  
pp. 4741-4755
Author(s):  
Steven Kregel ◽  
Pia Bagamasbad ◽  
Shihan He ◽  
Elizabeth LaPensee ◽  
Yemi Raji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Target Genes ◽  
Normal Growth ◽  
Differential Modulation ◽  
Expression Of Genes ◽  
Prostate Cancer Therapy ◽  
Specific Factors

Abstract Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.

scholarly journals Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

2009 ◽  
Vol 16 (1) ◽  
pp. 155-169 ◽  
Author(s):  
Kamilla Malinowska ◽  
Hannes Neuwirt ◽  
Ilaria T Cavarretta ◽  
Jasmin Bektic ◽  
Hannes Steiner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Interleukin 6 ◽  
Tumour Progression ◽  
Receptor Activity ◽  
Mitogen Activated Protein Kinase ◽  
Androgen Receptor Activity ◽  
Stimulation Of

It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.

scholarly journals Loss and revival of androgen receptor signaling in advanced prostate cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Nicolò Formaggio ◽  
Mark A. Rubin ◽  
Jean-Philippe Theurillat
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Poor Prognosis ◽  
Advanced Prostate Cancer ◽  
Molecular Mechanisms ◽  
Androgen Receptor Signaling ◽  
Androgen Synthesis ◽  
Prostate Cancer Therapy ◽  
Signaling Axis ◽  
Prostate Cancers

AbstractTargeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.

Improving the Outcome of Patients with Castration-resistant Prostate Cancer Through Rational Targeting of the Androgen Receptor

2009 ◽  
Vol 05 (01) ◽  
pp. 58
Author(s):  
Gerhardt Attard ◽  
Johann S De Bono ◽  
Chris Parker ◽  
◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Significant Proportion ◽  
Serum Levels ◽  
Castration Resistant Prostate Cancer ◽  
Common Cause ◽  
Receptor Signalling ◽  
Castration Resistant ◽  
Prostate Cancers ◽  
Related Mortality

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Recent evidence confirms that androgen receptor signalling continues to drive a significant proportion of progressing prostate cancers despite castrate serum levels of testosterone and multiple hormonal interventions. An increased understanding of the molecular biology underlying CRPC is informing on therapeutic targets for this disease, and we hypothesise that this will lead to the development of more efficacious drugs.

scholarly journals A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells

2019 ◽  
Vol 2 (4) ◽  
pp. e201800213 ◽  
Author(s):  
Serge Auvin ◽  
Harun Öztürk ◽  
Yusuf T Abaci ◽  
Gisele Mautino ◽  
Florence Meyer-Losic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Ex Vivo ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Issue ◽  
Castration Resistant ◽  
Clinical Resistance ◽  
Xenograft Models ◽  
Prostate Cancers

Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen–androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects’ importance in modulating drug activity in vivo.

scholarly journals Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2944
Author(s):  
Zoran Culig
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cellular Response ◽  
Target Genes ◽  
Neuroendocrine Differentiation ◽  
Cancer Tissue ◽  
Androgen Ablation ◽  
Prostate Cancers

Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.

scholarly journals SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Trnski ◽  
Maja Sabol ◽  
Sanja Tomić ◽  
Ivan Štefanac ◽  
Milanka Mrčela ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Androgen Receptor Activity ◽  
Signaling Activation ◽  
Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

scholarly journals A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Erik Bovinder Ylitalo ◽  
Elin Thysell ◽  
Mattias Landfors ◽  
Maria Brattsand ◽  
Emma Jernberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Bone Metastases ◽  
Metastatic Prostate Cancer ◽  
Tumor Biology ◽  
Receptor Activity ◽  
Mrna Levels ◽  
Androgen Receptor Activity ◽  
Patient Prognosis

Abstract Background Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity. Materials and methods Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity. Results Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT. Conclusions A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

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