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International Journal of Biological... 2023Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen...
Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen receptors (AR). However, the mechanisms by which AR affects hair follicles remain unclear. In our study, we found that miR-221 significantly suppressed hair growth and the proliferation of dermal papilla cells (DPCs) and dermal sheath cells (DSCs) in AGA patients. Interestingly, miR-221 and AR were mainly co-located in the same part of the hair follicle. Mechanistic analysis revealed that AR directly promoted the transcription of miR-221, which in turn suppressed IGF-1 expression, leading to the inactivation of the MAPK pathway in DPCs and the PI3K/AKT pathway in DSCs. In AGA patients, miR-221 expression was positively correlated with AR expression and negatively correlated with IGF-1 expression. Our findings indicate that miR-221, as a direct target of AR, plays a crucial role in the pathogenesis of AGA, making it a novel biomarker and potential therapeutic target for treating AGA.
Topics: Adult; Humans; Alopecia; Insulin-Like Growth Factor I; MicroRNAs; Phosphatidylinositol 3-Kinases; Receptors, Androgen
PubMed: 37496996
DOI: 10.7150/ijbs.80481 -
Frontiers in Endocrinology 2020
Topics: Animals; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Receptors, Androgen; Triple Negative Breast Neoplasms
PubMed: 33519718
DOI: 10.3389/fendo.2020.636480 -
International Journal of Biological... 2014
Topics: Androgens; Humans; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 24948878
DOI: 10.7150/ijbs.9576 -
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 -
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 -
Oncotarget Mar 2017Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen... (Review)
Review
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing. These AR splice variants are increased in cell and mouse models of CR-PCa and in CR-PCa tumors. Several AR variants lack the ligand binding domain, but retain their ability to bind DNA and activate transcription-linking constitutive AR function and therapeutic failure. ARV7 is the only variant endogenously detected at the protein level and thus has undergone more thorough molecular characterization. Clinical trials in PCa are currently investigating ARV7 utility as a biomarker and new therapeutics that inhibit ARV7 . Overall, this review will illustrate the historical perspectives of AR splice variant discovery using fundamental molecular biology techniques and how it changed the clinical approach to both therapeutic decisions and strategy. The body of work investigating AR splice variants in PCa represents a true example of translational research from bench to bedside.
Topics: Alternative Splicing; Humans; Male; Prostatic Neoplasms; Protein Isoforms; Receptors, Androgen
PubMed: 28077788
DOI: 10.18632/oncotarget.14537 -
The American Journal of Pathology Mar 2024Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by... (Review)
Review
Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by the functional consequences of AR point mutations and increased expression of constitutively active receptors. Many coactivators (>280) interact with different AR regions. Most studies have determined the expression of coactivators and their effects in the presence of increasing concentrations of androgen or the antiandrogen enzalutamide. The p160 group of coactivators (SRC-1, SRC-2, and SRC-3) is highly expressed in prostate cancer and contributes to ligand-dependent activation of the receptor in models that represent therapy-sensitive and therapy-resistant cell lines. The transcriptional coactivators p300 and CREB-binding protein (CBP) are implicated in the regulation of a large number of cellular events, such as proliferation, apoptosis, migration, and invasion. AR coactivators also may predict biochemical and clinical recurrence. The AR coactivator expression, which is enhanced in enzalutamide resistance, includes growth regulating estrogen receptor binding 1 (GREB1) and GATA-binding protein 2 (GATA2). Several coactivators also activate AR-unrelated signaling pathways, such as those of insulin-like growth factors, which inhibit apoptosis in cancer cells. They are expressed in multiple models of resistance to therapy and can be targeted by various inhibitors in vitro and in vivo. The role of the glucocorticoid receptor in endocrine therapy-resistant prostate cancer has been documented previously. Specific coactivators may interact with the glucocorticoid receptor, thus contributing to therapy failure.
Topics: Male; Humans; Androgens; Receptors, Androgen; Receptors, Glucocorticoid; Histone Acetyltransferases; Prostatic Neoplasms; Cell Line, Tumor; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38104650
DOI: 10.1016/j.ajpath.2023.12.003 -
Endocrinology Apr 2023The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where... (Review)
Review
The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor's potential as a therapeutic target and will help guide the development of new treatment approaches.
Topics: Humans; Male; Androgen Receptor Antagonists; Antineoplastic Agents; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction
PubMed: 37154098
DOI: 10.1210/endocr/bqad071 -
Cells Mar 2022Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex... (Review)
Review
Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at -regulatory enhancer regions to induce the spatiotemporal transcription of target genes. This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how -regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor.
Topics: Cell Line, Tumor; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Transcription, Genetic
PubMed: 35269520
DOI: 10.3390/cells11050898 -
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