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1.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799604

RESUMEN

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.


Asunto(s)
Proteína NEDD8/genética , Neoplasias de la Próstata/genética , Procesamiento Proteico-Postraduccional , Proteínas Quinasas Asociadas a Fase-S/genética , Factores de Transcripción de la Familia Snail/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclopentanos/farmacología , Docetaxel/farmacología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Proteína NEDD8/metabolismo , Clasificación del Tumor , Células PC-3 , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo
2.
Zhonghua Fu Chan Ke Za Zhi ; 56(4): 251-256, 2021 Apr 25.
Artículo en Chino | MEDLINE | ID: mdl-33902236

RESUMEN

Objective: To explore genetic counseling and prenatal diagnosis strategies for women who have androgen insensitivity syndrome (AIS) family history or pregnancy history of AIS proband. Methods: Three families of complete AIS (CAIS) were retrospectively reported and summarized. The subsequent pregnancies and processes of prenatal diagnosis were followed up. Results: Among three CAIS families, one family had androgen receptors (AR) gene mutation diagnosis; the other two families were diagnosed clinically without gene diagnosis. All three mothers of CAIS probands were in pregnant again when they sought counseling, with gestational weeks between 7-13 weeks. They underwent chorionic villi sampling or amniocentesis in their second trimester (at 12, 16, 17 weeks respectively). Chromosome gender of all three fetuses were 46,XY, which was inconsistent with the ultrasonographic phenotype of external genitalia. All patients chose selective abortion in their second trimester. The external genitalia of all aborted fetuses were female phenotype, which supported the diagnosis of CAIS. Conclusion: Genetic counseling and prenatal diagnosis should be provided to high-risk patients with family history of AIS or proband pregnancy history, so as to achieve the goal of good childbearing and sound childrearing.


Asunto(s)
Síndrome de Resistencia Androgénica , Síndrome de Resistencia Androgénica/diagnóstico , Síndrome de Resistencia Androgénica/genética , Femenino , Asesoramiento Genético , Humanos , Masculino , Proyectos Piloto , Embarazo , Diagnóstico Prenatal , Receptores Androgénicos/genética , Estudios Retrospectivos
3.
Eur J Med Chem ; 216: 113307, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652354

RESUMEN

Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 µM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t 1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Proteolisis , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/genética , Relación Estructura-Actividad , Tasa de Supervivencia , Trasplante Heterólogo , Pez Cebra/crecimiento & desarrollo , Pez Cebra/fisiología
4.
Eur J Med Chem ; 216: 113247, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652355

RESUMEN

As a newly emerged technology, PROTAC (proteolysis targeting chimera) is a promising therapeutic strategy for varieties of diseases. Unlike small molecule inhibitors, PROTACs catalytically induce target proteins degradation, including currently "undruggable" target proteins. In addition, PROTACs can be a potentially successful strategy to overcome drug resistance. IAPs can inhibit apoptosis by inhibiting caspase, and also exhibits the activity of E3 ubiquitin ligase. Specific and nongenetic IAP-based protein erasers (SNIPERs) are hybrid molecules that designed based on IAPs, and used to degrade the target proteins closely associated with diseases. Their structures consist of three parts, including target protein ligand, E3 ligase ligand and the linker between them. SNIPERs (PROTACs) degrade diseases-associated proteins through human inherent ubiquitin-proteasome system. So far, many SNIPERs have been developed to treat diseases that difficult to handle by traditional methods, such as radiotherapy, chemotherapy and small molecule inhibitors, and showed promising prospects in application. In this paper, the recent advances of SNIPERs were summarized, and the chances and challenges associated with this area were also highlighted.


Asunto(s)
Proteínas Inhibidoras de la Apoptosis/metabolismo , Ligandos , Antineoplásicos/química , Antineoplásicos/metabolismo , Proteínas Fetales/antagonistas & inhibidores , Proteínas Fetales/metabolismo , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Proteína Huntingtina/antagonistas & inhibidores , Proteína Huntingtina/metabolismo , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/metabolismo , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Receptores Estrogénicos/metabolismo
5.
Nat Med ; 27(3): 426-433, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664492

RESUMEN

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-ß signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Transcripción Genética/efectos de los fármacos , Biopsia , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo
6.
Nat Commun ; 12(1): 1979, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33785741

RESUMEN

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.


Asunto(s)
Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Tumores Neuroendocrinos/genética , Neoplasias de la Próstata/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Epigenómica/métodos , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Mutación , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/terapia , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Interferencia de ARN , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
7.
EBioMedicine ; 65: 103246, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33647767

RESUMEN

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.


Asunto(s)
/patología , Péptidos/genética , Receptores Androgénicos/genética , Anciano , Estudios de Casos y Controles , Cuidados Críticos/estadística & datos numéricos , Femenino , Genoma Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Índice de Severidad de la Enfermedad , España , Testosterona/sangre
8.
Am J Physiol Lung Cell Mol Physiol ; 320(5): L803-L818, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33719566

RESUMEN

Epidemiological studies demonstrate an apparent sex-based difference in the prevalence of asthma, with a higher risk in boys than girls, which is reversed postpuberty, where women become more prone to asthma than men, suggesting a plausible beneficial role for male hormones, especially androgens as a regulator of pathophysiology in asthmatic lungs. Using a murine model of asthma developed with mixed allergen (MA) challenge, we report a significant change in airway hyperresponsiveness (AHR), as demonstrated by increased thickness of epithelial and airway smooth muscle layers and collagen deposition, as well as Th2/Th17-biased inflammation in the airways of non-gonadectomized (non-GDX) and gonadectomized (GDX) male mice. Here, compared with non-GDX mice, MA-induced AHR and inflammatory changes were more prominent in GDX mice. Activation of androgen receptor (AR) using 5α-dihydrotestosterone (5α-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling-associated changes, resulting in improved lung function compared with MA alone challenged mice, especially in GDX mice. These changes were not observed with Flutamide (Flut, AR antagonist). Overall, we show that AR exerts a significant and beneficial role in asthma by regulating AHR and inflammation.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/complicaciones , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Inflamación/prevención & control , Receptores Androgénicos/metabolismo , Hipersensibilidad Respiratoria/prevención & control , Animales , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Androgénicos/genética , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Transducción de Señal
9.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652992

RESUMEN

Substances that can modify the androgen receptor pathway in humans and animals are entering the environment and food chain with the proven ability to disrupt hormonal systems and leading to toxicity and adverse effects on reproduction, brain development, and prostate cancer, among others. State-of-the-art databases with experimental data of human, chimp, and rat effects by chemicals have been used to build machine-learning classifiers and regressors and to evaluate these on independent sets. Different featurizations, algorithms, and protein structures lead to different results, with deep neural networks (DNNs) on user-defined physicochemically relevant features developed for this work outperforming graph convolutional, random forest, and large featurizations. The results show that these user-provided structure-, ligand-, and statistically based features and specific DNNs provided the best results as determined by AUC (0.87), MCC (0.47), and other metrics and by their interpretability and chemical meaning of the descriptors/features. In addition, the same features in the DNN method performed better than in a multivariate logistic model: validation MCC = 0.468 and training MCC = 0.868 for the present work compared to evaluation set MCC = 0.2036 and training set MCC = 0.5364 for the multivariate logistic regression on the full, unbalanced set. Techniques of this type may improve AR and toxicity description and prediction, improving assessment and design of compounds. Source code and data are available on github.


Asunto(s)
Aprendizaje Profundo , Unión Proteica/genética , Proteínas/genética , Receptores Androgénicos/genética , Algoritmos , Animales , Humanos , Ligandos , Modelos Logísticos , Redes Neurales de la Computación , Ratas , Programas Informáticos
10.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Anticancer Res ; 41(3): 1377-1386, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788729

RESUMEN

BACKGROUND/AIM: The purpose of this study was to examine the expression of estrogen receptor α (ERα) and ß (ERß), androgen receptor (AR), SIRT1, SIRT2 and SIRT3 in prostate cancer (PCa). MATERIALS AND METHODS: From October 2010 to January 2015, 70 patients who had undergone radical prostatectomy following a PCa diagnosis were enrolled in our study. Normal prostate tissue (NPT) and prostate cancer tissues (PCAT) were separated, and the expression of each receptor in each tissue was analyzed with immunochemical staining. Univariate and multivariate analyses were performed to identify factors affecting the development of PCa. RESULTS: ERß and AR were highly expressed in PCAT compared with NPT (p<0.05). SIRT2 was highly expressed in NPT and PCAT (p<0.05). Univariate and multivariate analyses showed that AR and SIRT2 affect PCa development. CONCLUSION: AR is a risk factor for PC, and SIRT2 is associated with a lower incidence of PCa.


Asunto(s)
Receptor alfa de Estrógeno/biosíntesis , Receptor beta de Estrógeno/biosíntesis , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Sirtuina 1/biosíntesis , Sirtuina 2/biosíntesis , Sirtuina 3/biosíntesis , Anciano , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía
12.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672769

RESUMEN

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Proteolisis/efectos de los fármacos
13.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658518

RESUMEN

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Masculino , Adhesión en Parafina , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Matrices Tisulares , Transcriptoma
14.
J Med Chem ; 64(3): 1570-1583, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523674

RESUMEN

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Andrógenos/toxicidad , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Receptores Androgénicos/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
15.
J Steroid Biochem Mol Biol ; 208: 105834, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33548461

RESUMEN

Androgens are critical for male sex differentiation. Their actions are mediated by the androgen receptor (AR). Mutations disrupting AR function result in the androgen insensitivity syndrome (AIS). In this study, we identified in a patient with complete AIS, a novel AR mutation p.R856L. To investigate the functional properties of p.R856L, we performed functional studies. In comparison, we have characterized two already described mutations: p.R856H and p.R856C. We used a model composed of two different promoters fused to a reporter gene, two cell lines, and showed that all mutations were able to transactivate the (ARE)2-TATA promoter expressed in CHO cells more highly. Moreover, we confirmed the pathogenicity of the p.R856L and p.R856C mutations, and their associations with complete AIS. In contrast, the p.R856H mutation, which is associated with a spectrum of AIS phenotypes, showed less severe transcriptional constraints. Altogether, our studies allowed us to better characterize arginine residue at p.R856 position.


Asunto(s)
Síndrome de Resistencia Androgénica/genética , Andrógenos/genética , Receptores Androgénicos/genética , Diferenciación Sexual/genética , Secuencia de Aminoácidos/genética , Síndrome de Resistencia Androgénica/patología , Andrógenos/metabolismo , Animales , Arginina/genética , Cricetinae , Cricetulus , Humanos , Ligandos , Masculino , Mutación/genética , Dominios Proteicos/genética
16.
Artículo en Inglés | MEDLINE | ID: mdl-33557243

RESUMEN

Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERß) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.


Asunto(s)
Disruptores Endocrinos , Andrógenos/toxicidad , Disruptores Endocrinos/toxicidad , Estrógenos/toxicidad , Femenino , Masculino , Receptores Androgénicos , Receptores Estrogénicos
17.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546359

RESUMEN

(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of mothers whose pups were taken away immediately after parturition and did not exhibit caring behavior 10 days later. (3) Results: Differentially expressed genes were found and validated by quantitative RT-PCR, among them NACHT and WD repeat domain containing 1 (Nwd1) is known to control androgen receptor (AR) protein levels. The distribution of Nwd1 mRNA and AR was similar in the preoptic area. Therefore, we focused on this steroid hormone receptor and found its reduced protein level in rat dams. To establish the function of AR in maternal behavior, its antagonist was administered intracerebroventricularly into mother rats and increased pup-directed behavior of the animals. (4) Conclusions: AR levels are suppressed in the preoptic area of mothers possibly mediated by altered Nwd1 expression in order to allow sustained high-level care for the pups. Thus, our study first implicated the AR in the control of maternal behaviors.


Asunto(s)
Conducta Materna , Periodo Posparto , Área Preóptica/metabolismo , Receptores Androgénicos/fisiología , Animales , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Madres , Ratas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Secuencia de ARN
18.
Cancer Sci ; 112(5): 1899-1910, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33619826

RESUMEN

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Transportador de Glucosa de Tipo 4/metabolismo , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores de Glucocorticoides/metabolismo , Antagonistas de Receptores Androgénicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/metabolismo , Transportador de Glucosa de Tipo 4/antagonistas & inhibidores , Humanos , Masculino , Feniltiohidantoína/uso terapéutico , Receptores Androgénicos/metabolismo , Regulación hacia Arriba
20.
Sensors (Basel) ; 21(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572727

RESUMEN

In recent years, there has been an increasing demand for predictive and sensitive in vitro tools for drug discovery. Split complementation assays have the potential to enlarge the arsenal of in vitro tools for compound screening, with most of them relying on well-established reporter gene assays. In particular, ligand-induced complementation of split luciferases is emerging as a suitable approach for monitoring protein-protein interactions. We hereby report an intracellular nanosensor for the screening of compounds with androgenic activity based on a split NanoLuc reporter. We also confirm the suitability of using 3D spheroids of Human Embryonic Kidney (HEK-293) cells for upgrading the 2D cell-based assay. A limit of detection of 4 pM and a half maximal effective concentration (EC50) of 1.7 ± 0.3 nM were obtained for testosterone with HEK293 spheroids. This genetically encoded nanosensor also represents a new tool for real time imaging of the activation state of the androgen receptor, thus being suitable for analysing molecules with androgenic activity, including new drugs or endocrine disrupting molecules.


Asunto(s)
Andrógenos , Mediciones Luminiscentes , Nanotecnología , Receptores Androgénicos , Genes Reporteros , Células HEK293 , Humanos , Luciferasas/genética , Receptores Androgénicos/genética
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