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Endocrine-related Cancer Aug 2014The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is... (Review)
Review
The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.
Topics: Animals; Humans; Phosphorylation; Protein Kinases; Protein Structure, Tertiary; Receptors, Androgen
PubMed: 24424504
DOI: 10.1530/ERC-13-0472 -
International Journal of Molecular... Jan 2022The role of endocrine disruptors (EDs) in the human prostate gland is an overlooked issue even though the prostate is essential for male fertility. From experimental... (Review)
Review
The role of endocrine disruptors (EDs) in the human prostate gland is an overlooked issue even though the prostate is essential for male fertility. From experimental models, it is known that EDs can influence several molecular mechanisms involved in prostate homeostasis and diseases, including prostate cancer (PCa), one of the most common cancers in the male, whose onset and progression is characterized by the deregulation of several cellular pathways including androgen receptor (AR) signaling. The prostate gland essentiality relies on its function to produce and secrete the prostatic fluid, a component of the seminal fluid, needed to keep alive and functional sperms upon ejaculation. In physiological condition, in the prostate epithelium the more-active androgen, the 5α-dihydrotestosterone (DHT), formed from testosterone (T) by the 5α-reductase enzyme (SRD5A), binds to AR and, upon homodimerization and nuclear translocation, recognizes the promoter of target genes modulating them. In pathological conditions, AR mutations and/or less specific AR binding by ligands modulate differently targeted genes leading to an altered regulation of cell proliferation and triggering PCa onset and development. EDs acting on the AR-dependent signaling within the prostate gland can contribute to the PCa onset and to exacerbating its development.
Topics: Animals; Endocrine Disruptors; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 35163140
DOI: 10.3390/ijms23031216 -
Molecular Human Reproduction May 2023Currently, our understanding of hormonal regulation within the female reproductive system is largely based on our knowledge of estrogen and progesterone signalling.... (Review)
Review
Currently, our understanding of hormonal regulation within the female reproductive system is largely based on our knowledge of estrogen and progesterone signalling. However, while the important functions of androgens in male physiology are well known, it is also recognized that androgens play critical roles in the female reproductive system. Further, androgen signalling is altered in a variety of gynaecological conditions, including endometriosis and polycystic ovary syndrome, indicative of regulatory roles in endometrial and ovarian function. Co-regulatory mechanisms exist between different androgens, estrogens, and progesterone, resulting in a complex network of steroid hormone interactions. Evidence from animal knockout studies, in vitro experiments, and human data indicate that androgen receptor expression is cell-specific and menstrual cycle stage-dependent, with important regulatory roles in the menstrual cycle, endometrial biology, and follicular development in the ovaries. This review will discuss the expression and co-regulatory interactions of androgen receptors, highlighting the complexity of the androgen signalling pathway in the endometrium and ovaries, and the synthesis of androgens from additional alternative pathways previously disregarded as male-specific. Moreover, it will illustrate the challenges faced when studying androgens in female biology, and the need for a more in-depth, integrative view of androgen metabolism and signalling in the female reproductive system.
Topics: Animals; Male; Female; Humans; Androgens; Ovary; Progesterone; Endometrium; Estrogens; Receptors, Androgen
PubMed: 37171897
DOI: 10.1093/molehr/gaad017 -
Endocrine-related Cancer Sep 2017Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen... (Review)
Review
Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or more variants can be co-expressed in the same cell under many circumstances, which raises the question of how these variants physically and functionally interact with the full-length receptor or one another in the course of PCa progression. To address this issue, in this review, we will characterize and discuss androgen receptor variants, including the novel variants discovered in the last couple of years (i) individually, (ii) with respect to their physical and functional interaction with one another and (iii) in clinical relevance. Here, we also introduce the very recent understanding of AR-Vs obtained through successful development of some AR-V-specific antibodies as well as identification of novel AR-Vs by data mining approaches.
Topics: Animals; Humans; Male; Prostatic Neoplasms; Protein Multimerization; Receptors, Androgen; Transcriptome
PubMed: 28808043
DOI: 10.1530/ERC-17-0108 -
American Journal of Physiology. Cell... Sep 2022The effects of androgens have been extensively studied in a variety of organs and cell types with an increasing focus on the sexually dimorphic role androgens play not... (Review)
Review
The effects of androgens have been extensively studied in a variety of organs and cell types with an increasing focus on the sexually dimorphic role androgens play not only with respect to cellular functions but also in metabolism. Although the classical mechanism of androgen action is via ligand-dependent binding with the nuclear transcription factor, androgen receptor (AR), cytosolic AR can also activate second messenger signaling pathways. Given that cytosolic AR can signal in this manner, there has been increased interest in the mechanisms by which androgens may control cellular organelle function. This review highlights the effects that androgens have on mitochondrial structure and function with emphasis on biogenesis, fusion/fission, mitophagy, bioenergetics (oxidative phosphorylation), and reactive oxygen species production. There are a number of publications on the effects of androgens in these general areas of mitochondrial function. However, the precise mechanisms by which androgens cause these effects are not known. In addition, given that the nucleus and mitochondria work in tandem to control mitochondrial function and the mitochondria have their own DNA, future research efforts should focus on the direct, mechanistic effects of androgens on mitochondrial function.
Topics: Androgens; Mitochondria; Oxidative Phosphorylation; Receptors, Androgen; Signal Transduction
PubMed: 35704694
DOI: 10.1152/ajpcell.00205.2022 -
Computational Biology and Chemistry Jun 2021There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart...
There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 μM dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.
Topics: Androgen Receptor Antagonists; Humans; Ligands; Models, Molecular; Receptors, Androgen; Tumor Cells, Cultured
PubMed: 33932781
DOI: 10.1016/j.compbiolchem.2021.107490 -
Cancer Letters Nov 2015Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy... (Review)
Review
Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy represents the mainstay of treatment. Paradoxically, the advent of a wave of antiestrogens eclipsed the therapeutic potential of alternative therapeutic options. At the beginning of the hormonal therapy era the administration of antiandrogens to metastatic male breast cancer patients was proposed. Ever since the use of these compounds has largely been neglected. A therapeutic role for antiandrogens has been envisioned again in recent years. First, molecular characterization efforts pointed to the androgen receptor as a potential therapeutic target. Second, the development of aromatase inhibitors unexpectedly raised the need for neutralizing androgens in order to tackle endocrine feedback mechanisms responsible for acquired resistance. We herein provide an overview of molecular studies where the androgen receptor was investigated at the genomic, transcriptomic or phenotypic level. We then discuss androgens in the context of the endocrine networks nourishing male breast cancer. Finally, clinical evidence on antiandrogens is summarized along with strategies should be implemented to improve the medical management of these patients.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms, Male; Humans; Male; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Receptors, Androgen; Signal Transduction; Treatment Outcome
PubMed: 26276719
DOI: 10.1016/j.canlet.2015.07.040 -
Oncotarget Apr 2017Ovarian cancer is the major cause of death in women with gynecologic malignancies. There is emerging evidence that Androgen/androgen receptor (AR) signaling plays a... (Review)
Review
Ovarian cancer is the major cause of death in women with gynecologic malignancies. There is emerging evidence that Androgen/androgen receptor (AR) signaling plays a critical role in the etiology and progression of this disease. Androgen receptor is frequently expressed in various subtypes of ovarian cancers and androgen/AR signaling has been shown to promote proliferation, migration, and invasion of ovarian cancer cells. Furthermore, shorter AR CAG repeats length and increased AR activity are associated with increased ovarian cancer risk and may be a useful prognosticator under certain circumstances. Here, we summarize current findings regarding the role of the AR in ovarian cancer and discuss agents that target this pathway as potential therapeutics for ovarian cancer.
Topics: Carcinogenesis; Female; Humans; Ovarian Neoplasms; Polymorphism, Genetic; Receptors, Androgen
PubMed: 27741511
DOI: 10.18632/oncotarget.12561 -
Frontiers in Endocrinology 2023In females, androgens contribute to ovarian diseases such as polycystic ovarian syndrome (PCOS), but their action is also crucial for ovarian physiology, i.e.,...
In females, androgens contribute to ovarian diseases such as polycystic ovarian syndrome (PCOS), but their action is also crucial for ovarian physiology, i.e., follicular growth and estradiol (E2) synthesis during reproductive life, in interaction with the gonadotropins LH and FSH. However, it is unclear whether androgens already play a role in the ovary at mini-puberty, a phase of postnatal development with active follicular growth and high E2 levels. Therefore, we analyzed the potential actions of androgens on the ovary and their possible interaction with gonadotropins during this period in mice. We used molecular-based studies and pharmacological approaches and on cultured ovaries. We found that mini-pubertal ovaries produce significant amounts of testosterone and display androgen receptor (AR) expression in growing follicles, both under the control of LH. By blocking AR signaling either or in ovarian cultures, we found that this pathway may participate in the regulation of prepubertal E2 synthesis and follicular growth, possibly by regulating the expression of a number of key intra-ovarian regulators, including FSH receptor (), the aromatase enzyme converting androgens into estrogens ( and the cell cycle inhibitor p27KIP1 (. We further showed that AR may stimulate FSH-mediated regulation of through its action on mRNA abundance. Overall, this work supports the idea that AR signaling is already activated in mini-pubertal ovaries to regulate E2 synthesis and follicular growth, at the interplay with LH and FSH signaling. Its early action may, thus, contribute to the implementation of early ovarian function with possible impacts on reproductive function.
Topics: Animals; Female; Mice; Androgens; Follicle Stimulating Hormone; Gonadotropins; Ovary; Receptors, Androgen; Sexual Maturation
PubMed: 37152943
DOI: 10.3389/fendo.2023.1130681 -
Nucleic Acids Research Jan 2023Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust...
Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.
Topics: Male; Humans; Receptors, Androgen; Androgens; Transcription Factors; Gene Expression Regulation; Prostatic Neoplasms; Gene Expression; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 36535377
DOI: 10.1093/nar/gkac1158