scholarly journals Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jianneng Li ◽  
Mohammad Alyamani ◽  
Ao Zhang ◽  
Kai-Hsiung Chang ◽  
Michael Berk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Tumor Cells ◽  
Target Genes ◽  
Hydroxysteroid Dehydrogenase ◽  
Mouse Xenograft ◽  
Ubiquitin E3 Ligase ◽  
Metabolic Mechanism ◽  
Stimulation Of

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

Aberrant tumor metabolism to enable glucocorticoid receptor takeover in enzalutamide-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 157-157
Author(s):  
Nima Sharifi ◽  
Jianneng Li ◽  
Mohammad Alyamani ◽  
Ao Zhang ◽  
Kai-Hsiung Chang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
High Performance ◽  
Therapeutic Effects ◽  
Ubiquitin E3 Ligase ◽  
Xenograft Models ◽  
Metabolic Mechanism ◽  
Cancer Tissues ◽  
Expression Loss ◽  
Stimulation Of

157 Background: Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs progression-free and overall survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of approximately 50% of genes normally stimulated by AR, thereby permitting continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. Methods: We assessed the effects of enzalutamide on metabolism of cortisol to cortisone in the LAPC4 and VCaP models of prostate cancer using [3H]-cortisol and high performance liquid chromatography. Expression of 11β-hydroxysteroid dehydrogenase-2, encoding the enzyme 11βHSD2, which converts cortisol to cortisone, was assessed by immunoblot, in models of prostate cancer, tissues from patients treated with enzalutamide and prostate tissues treated exogenously with enzalutamide. The effect of shRNA knockdown of the AMFR ubiquitin E3-ligase on 11βHSD2 protein expression and enzyme activity was assessed. Finally, the potential therapeutic effects of 11βHSD2 re-expression on enzalutamide resistance was assessed in xenograft models. Results: Enzalutamide impedes inactivation of cortisol to cortisone, thereby sustaining tumor cortisol concentrations, permitting GR stimulation and enzalutamide resistance. Impeded cortisol inactivation by enzalutamide occurs by way of 11β-HSD2 expression loss in models of prostate cancer, prostate tissues from enzalutamide-treated patients and fresh prostatic tissues treated exogenously with enzalutamide. AMFR mediates loss of 11β-HSD2, which otherwise inactivates cortisol. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Conclusions: Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

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.

Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells

2010 ◽  
Vol 297 (2) ◽  
pp. 226-230 ◽  
Author(s):  
Itsuhiro Takizawa ◽  
Tsutomu Nishiyama ◽  
Noboru Hara ◽  
Tatsuhiko Hoshii ◽  
Fumio Ishizaki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Agonistic Activity

scholarly journals Isoform specific activities of androgen receptor and its splice variants in prostate cancer cells

Endocrinology ◽  
2020 ◽  
Author(s):  
Harika Nagandla ◽  
Matthew J Robertson ◽  
Vasanta Putluri ◽  
Nagireddy Putluri ◽  
Cristian Coarfa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Gene ◽  
Target Genes ◽  
Splice Variants ◽  
Clinical Samples ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Activities ◽  
Lncap Prostate Cancer Cell

Abstract Androgen receptor (AR) signaling continues to drive castration resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and AR v567es are two of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or AR v567es to delineate similarities and differences in transcriptomics, metabolomics and lipidomics resulting from the activation of AR, ARv7 or AR v567es. While the majority of target genes were similarly regulated by the action of all three isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and AR v567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.

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