Effects of steroidal and non‐steroidal antiandrogens on wild‐type and mutant androgen receptors

Urushibara, Masayasu; Ishioka, Junichiro; Hyochi, Nobuhiko; Kihara, Kazunori; Hara, Shuntaro; Singh, Pratap; Isaacs, John T.; Kageyama, Yukio

doi:10.1002/pros.20542

Cited by 32 publications

(35 citation statements)

References 16 publications

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“…1, 1, or 10 nM). In order to see the complete effect of HF, the dose chosen was 1000-10 000 times higher concentration than that of DHT (Yamamoto et al 2000, Urushibara et al 2007. Pretreatment with HF repressed ERK phosphorylation significantly in DHT-treated cells compared with control.…”

Section: Erk1/2 Is Activated By Dht Via An Ar-mediated Mechanismmentioning

confidence: 99%

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Hamzeh¹,

Robaire²

2011

Journal of Endocrinology

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Androgens are the primary regulators of epididymal structure and functions. In the classical view of androgen action, binding of androgen to the intracellular androgen receptor (AR) produces the receptor-steroid complex that has high affinity for DNA response elements and regulates the transcription of target genes. In this study, we demonstrate that in epididymal cells, 5a-dihydrotestosterone (DHT) can cause an alternative and rapid response that is independent of AR-DNA interactions and is mediated by activation of signaling pathways through the AR. We examined changes in AKT and extracellular signal-regulated protein kinases (ERK1/2) activation at early time points after DHT supplementation in the mouse proximal caput epididymis-1 cell line. DHT had no significant effect on AKT activation at any time point. However, DHT activated the ERK pathway as early as at 1 min, the pathway remained activated at 10 min, but activation was not sustained at later time points. Interestingly, ERK activation was blocked by hydroxyflutamide (HF), indicating that early ERK activation was an AR-mediated response. DHT phosphorylates steroid receptor co-activator (SRC) kinase, and this activation was required for the ERK response. EGFR and IGF1R were downstream of SRC, and these two receptors together contributed to enhance ERK and cAMP response elementbinding protein (CREB) phosphorylation. We postulate that this rapid action of androgen may ultimately act to modulate the transcription of genes regulated by AR in the nucleus. These results support the hypothesis that DHT can activate a pathway involving the sequential activation of MEK, ERK1/2, and CREB through the EGFR/IGF1R in an epididymal cell line.

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Section: Erk1/2 Is Activated By Dht Via An Ar-mediated Mechanismmentioning

confidence: 99%

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Hamzeh¹,

Robaire²

2011

Journal of Endocrinology

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“…The T877A mutation decreases AR ligand specificity and allows other steroids like estrogens, progestogens, and adrenal androgens, but also antiandrogens like OH-flutamide to act as agonists (25)(26)(27). Similarly, in patients treated with antiandrogen bicalutamide a tryptophan to cysteine substitution (W741C) can be found (28,29), which leads to AR activation by bicalutamide (25,30,31). A third prostate cancer AR mutation affecting its ligand specificity, a leucine-histidine substitution at position 701 (L701H), was found in two independent patients and the MDA PCa 2A prostate cancer cell line (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

A multi‐parameter imaging assay identifies different stages of ligand‐induced androgen receptor activation

et al. 2013

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Androgens exert their key function in development and maintenance of the male phenotype via the androgen receptor (AR). Ligand-activated ARs also play a role in prostate cancer. Despite initial success of treatment by testosterone depletion or blocking of androgen binding to the AR using antiandrogens, eventually all tumors escape to a therapy resistant stage. Development of novel therapies by other antagonistic ligands or compounds that target events subsequent to ligand binding is very important. Here, we validate a fluorescence resonance energy transfer (FRET) based imaging assay for ligand-induced AR activity, based on the conformational change in the AR caused by interaction between the FQNLF motif in the N-terminal domain and the cofactor binding groove in the ligand-binding domain (N/C-interaction). We test the assay using known agonistic and antagonistic ligands on wild type AR and specific AR mutants. Our data show a strong correlation between the ligand-induced AR N/C-interaction and transcriptional activity in wild type AR, but also in AR mutants with broadened ligand responsiveness. Moreover, we explore additional readouts of this assay that contribute to the understanding of the working mechanism of the ligands. Together, we present a sensitive assay that can be used to quantitatively assess the activity of agonistic and antagonistic AR ligands. ' 2013 International Society for Advancement of Cytometry Key terms androgen receptor; recurrent prostate cancer; ligand; N/C-interaction; quantitative live cell imaging; FRET

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“…44 Flutamide-treated LNCaP cells are therefore unable to transactivate AR-responsive genes, leading to growth inhibition. 45,46 Levels of AR in the nucleus and cytoplasm were monitored by Western blot in DHT-treated LNCaP cells in the presence and absence of C comatus extracts. The C comatus extracts did not affect the ability of AR to translocate into the nucleus, indicating that this is not the mechanism of action of these extracts.…”

Section: Discussionmentioning

confidence: 99%

The Culinary-Medicinal Mushroom Coprinus comatus as a Natural Antiandrogenic Modulator

2010

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Prostate cancer is the most common cancer diagnosed in men. Chemotherapy, androgen ablation, and androgen antagonist treatments have proven to have significant effects in the early stages of prostate cancer, whereas advanced prostate cancer is resilient to such treatments. The androgen receptor (AR), a ligand-dependent transcription factor, is the major drug target of prostate cancer therapy. Transition to the androgen-independent stage involves the activation of signaling pathways, AR gene mutations, and other mechanisms. Higher basidiomycetes mushrooms have been used since ancient times in folk medicine to treat a diversity of diseases, including cancer. The present study evaluates the antiandrogenic activity of different Coprinus comatus strains in their ability to interfere with AR function. The authors found that the most active extract was C comatus strain 734 extracted with hexane (CC734-H). This extract was able to (1) inhibit AR-mediated reporter activity, (2) inhibit the proliferation and viability of the LNCaP cell line, and (3) inhibit the colony formation of the LNCaP cell line, in comparison to the DU-145, PC-3, and MDA-Kb2 cells. In addition, CC734-H was able to reduce AR levels and prostate-specific antigen gene expression in the LNCaP-treated cell line. This study illustrates the potential of the C comatus mushroom as a natural antiandrogenic modulator that could serve in the treatment of prostatic diseases.

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Effects of steroidal and non‐steroidal antiandrogens on wild‐type and mutant androgen receptors

Abstract: Switching antiandrogens may be reasonable in prostate cancer with mutant ARs.

Cited by 32 publications

References 16 publications

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

A multi‐parameter imaging assay identifies different stages of ligand‐induced androgen receptor activation

The Culinary-Medicinal Mushroom Coprinus comatus as a Natural Antiandrogenic Modulator

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