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The Journal of Endocrinology Apr 2016Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes,... (Review)
Review
Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender among others. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with a clear gender difference. Here, we summarize the effects of androgen/AR on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as the metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension, and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles in strokes, depending on different kinds of factors; however, generally males have a higher incidence of strokes than females. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency causes elevated lipid accumulation to enhance atherosclerosis; however, targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in AAA development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy compared with age-matched women that may be due to androgens. Finally, androgen/AR plays important roles in contributing to obesity and insulin/leptin resistance to increase the metabolic syndrome.
Topics: Animals; Cardiovascular Diseases; Humans; Receptors, Androgen
PubMed: 26769913
DOI: 10.1530/JOE-15-0518 -
Best Practice & Research. Clinical... Aug 2015Androgens such as testosterone are steroid hormones essential for normal male reproductive development and function. Mutations of androgen receptors (AR) are often found... (Review)
Review
Androgens such as testosterone are steroid hormones essential for normal male reproductive development and function. Mutations of androgen receptors (AR) are often found in patients with disorders of male reproductive development, and milder mutations may be responsible for some cases of male infertility. Androgens exert their action through AR and its signalling in the testis is essential for spermatogenesis. AR is not expressed in the developing germ cell lineage so is thought to exert its effects through testicular Sertoli and peri-tubular myoid (PTM) cells. AR signalling in spermatogenesis has been investigated in rodent models where testosterone levels are chemically supressed or models with transgenic disruption of AR. These models have pinpointed the steps of spermatogenesis that require AR signalling, specifically maintenance of spermatogonial numbers, blood-testis barrier integrity, completion of meiosis, adhesion of spermatids and spermiation, together these studies detail the essential nature of androgens in the promotion of male fertility.
Topics: Animals; Humans; Infertility, Male; Male; Mutation; Receptors, Androgen; Spermatogenesis
PubMed: 26303086
DOI: 10.1016/j.beem.2015.04.006 -
International Journal of Molecular... Sep 2020Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation... (Review)
Review
Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
Topics: Energy Metabolism; Humans; Lysine Acetyltransferase 5; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 32927797
DOI: 10.3390/ijms21186622 -
The Journal of Endocrinology Mar 2015Androgen receptor (AR) is a ligand-inducible transcription factor, and a member of the steroid-thyroid-retinoid receptor superfamily, that mediates the biological... (Review)
Review
Androgen receptor (AR) is a ligand-inducible transcription factor, and a member of the steroid-thyroid-retinoid receptor superfamily, that mediates the biological effects of androgens in a wide range of physiological and pathological processes. AR expression was identified in vascular cells nearly 20 years ago, and recent research has shown that AR mediates a variety of actions of androgens in endothelial and vascular smooth muscle cells. In this mini-review, we review evidence indicating the importance of AR in human endothelial cell (HUVEC) homeostatic and pathogenic processes. Although a role for AR in the modulation of HUVEC biology is evident, the molecular mechanisms by which AR regulates HUVEC homeostasis and disease processes are not fully understood. Understanding these mechanisms could provide critical insights into the processes of pathogenesis of diseases ranging from cardiovascular disease to cancer that are major causes of human morbidity and mortality.
Topics: Endothelial Progenitor Cells; Human Umbilical Vein Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Androgen
PubMed: 25563353
DOI: 10.1530/JOE-14-0611 -
Journal of Experimental & Clinical... Jul 2023Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage...
BACKGROUND
Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed.
METHODS
Androgen-dependent (LNCaP) and -independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy.
RESULTS
We demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression.
CONCLUSIONS
We identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.
Topics: Male; Humans; Animals; Mice; Receptors, Androgen; Prostatic Neoplasms; Androgens; Androgen Antagonists; GATA2 Transcription Factor; Nitriles; Androgen Receptor Antagonists; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Nuclear Proteins
PubMed: 37507762
DOI: 10.1186/s13046-023-02769-z -
Journal of Molecular Neuroscience : MN Mar 2016Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor... (Review)
Review
Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients.
Topics: Bulbo-Spinal Atrophy, X-Linked; Humans; Motor Neurons; Receptors, Androgen
PubMed: 26547319
DOI: 10.1007/s12031-015-0674-7 -
Expert Review of Anticancer Therapy Sep 2018Five new agents have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer, including two targeting androgen receptor signaling... (Review)
Review
Five new agents have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer, including two targeting androgen receptor signaling (abiraterone acetate plus prednisone; enzalutamide). Recognition that these tumors remain driven by androgen receptor signaling has prompted clinical evaluation of these agents at earlier states in the prostate cancer disease continuum, along with the continued development of new agents targeting this pathway. Areas covered: This article focuses on apalutamide, a next-generation nonsteroidal antiandrogen, with current literature queried in PubMed/Medline. A narrative review strategy describes studies from engineering of the compound through to a 5-year outlook. Expert commentary: In the phase III SPARTAN study, apalutamide significantly improved metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer - the first treatment approved by the US Food and Drug Administration for this indication. Phase III studies are under way to determine the clinical benefit of apalutamide in other disease states. Given the multiplicity of prostate cancer treatment options now available, there is a need to maximize individual patient benefit through the development and validation of predictive biomarkers of sensitivity to drugs that can be used in real time to determine the optimal sequence and combinations of treatments for patients in need.
Topics: Androgen Receptor Antagonists; Animals; Biomarkers, Tumor; Drug Development; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Survival Rate; Thiohydantoins
PubMed: 30101644
DOI: 10.1080/14737140.2018.1503954 -
Asian Journal of Andrology 2019The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen... (Review)
Review
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
Topics: Antineoplastic Agents, Phytogenic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids
PubMed: 29900882
DOI: 10.4103/aja.aja_37_18 -
Frontiers in Endocrinology 2022Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the... (Review)
Review
Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the way to tackle specifically AR-positive BC patients. The prognostic and predictive role of AR in BC is a matter of debate, since the results from clinical trials are not striking, probably due to both technical and biological reasons. In this review, we aimed to highlight WHAT is AR, describing its structure and functions, WHAT to test and HOW to detect AR, WHERE AR should be tested (on primary tumor or metastasis) and WHY studying this fascinating hormone receptor, exploring and debating on its prognostic and predictive role. We considered AR and its ratio with other hormone receptors, analyzing also studies including patients with ductal carcinoma and with early and advanced BC, as well. We also emphasized the effects that both other hormone receptors and the newly emerging androgen-inducible non coding RNAs may have on AR function in BC pathology and the putative implementation in the clinical setting. Moreover, we pointed out the latest results by clinical trials and we speculated about the use of anti-AR therapies in BC clinical practice.
Topics: Androgens; Breast Neoplasms; Female; Humans; Prognosis; Receptors, Androgen
PubMed: 36111296
DOI: 10.3389/fendo.2022.977331 -
Clinical Pharmacokinetics Aug 2023Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer... (Review)
Review
Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug-drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure-response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins; Androgen Receptor Antagonists
PubMed: 37458966
DOI: 10.1007/s40262-023-01268-w