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1.
Anesthesiology ; 133(4): 852-866, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32930727

RESUMEN

BACKGROUND: Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. METHODS: Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). RESULTS: Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). CONCLUSIONS: Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.


Asunto(s)
Anestésicos por Inhalación/toxicidad , Isoflurano/toxicidad , Receptores Androgénicos/fisiología , Miembro 2 de la Familia de Transportadores de Soluto 12/fisiología , Factores de Edad , Antagonistas de Receptores Androgénicos/farmacología , Animales , Animales Recién Nacidos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Sprague-Dawley , Factores Sexuales
2.
Prog Urol ; 30(10): 484-487, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32620366

RESUMEN

COVID-19 is the pandemic that hit the world starting December 2019. Recent studies and international statistics have shown an increased prevalence, morbidity as well as mortality of this disease in male patients compared to female patients. The aim of this brief communication is to describe the pathophysiology of this sex-discrepancy, based on the infectivity mechanism of the coronavirus including the Angiotensin-Converting Enzyme 2 (ACE2), the Type II transmembrane Serine Protease (TMPRSS2), and the androgen receptor. This could help understand the susceptibility of urological patients, especially those receiving androgen deprivation therapy for prostate cancer, and testosterone replacement therapy.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/etiología , Pandemias , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/etiología , Receptores Androgénicos/fisiología , Receptores Virales/fisiología , Serina Endopeptidasas/fisiología , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/fisiología , Antineoplásicos Hormonales/uso terapéutico , Betacoronavirus/aislamiento & purificación , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Infecciones por Coronavirus/epidemiología , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Especificidad de Órganos , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , Neumonía Viral/epidemiología , Neoplasias de la Próstata/fisiopatología , Sistema Renina-Angiotensina/fisiología , Semen/virología , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/genética , Distribución por Sexo , Glicoproteína de la Espiga del Coronavirus/fisiología , Internalización del Virus
3.
J Steroid Biochem Mol Biol ; 196: 105493, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31614207

RESUMEN

17ß-Hydroxysteroid dehydrogenases (17ß-HSDs) catalyze the reduction of 17-ketosteroids and the oxidation of 17ß-hydroxysteroids to regulate the production of androgens and estrogens. Among them, 17ß-HSD type 3 (HSD17B3) is expressed almost exclusively in testicular Leydig cells and contributes to development of male sexual characteristics by converting androstenedione (A4) to testosterone (T). Mutations of HSD17B3 genes cause a 46,XY disorder of sexual development (46,XY DSD) as a result of low T production. Therefore, the evaluation of 17ß-HSD3 enzymatic activity is important for understanding and diagnosing this disorder. We adapted a method that easily evaluates enzymatic activity of 17ß-HSD3 by quantifying the conversion from A4 to T using androgen receptor (AR)-mediated transactivation. HEK293 cells were transduced to express human HSD17B3, and incubated medium containing A4. Depending on the incubation time with HSD17B3-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the AR expression vector and androgen-responsive reporter. Culture medium from HSD17B1 and HSD17B5-expressing cells also increased the luciferase activities. This system is also applicable to detect the conversion of 11-ketoandrostenedione to 11-ketotestosterone by HSD17B3. Establishment of HEK293 cells expressing various missense mutations in the HSD17B3 gene associated with 46,XY DSD revealed that this system is effective to evaluate the enzymatic activities of mutant proteins.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Receptores Androgénicos/fisiología , Activación Transcripcional/genética , 17-Hidroxiesteroide Deshidrogenasas/genética , Animales , Células Cultivadas , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/metabolismo , Activación Enzimática/genética , Inducción Enzimática/genética , Células HEK293 , Humanos , Mutación Missense/fisiología , Transfección
4.
J Steroid Biochem Mol Biol ; 196: 105496, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31655180

RESUMEN

Testosterone (T) is the predominant endogenous androgen in the bloodstream. At the vascular level, T presents genomic and non-genomic effects, and both effects may overlap. The genomic actions assume that androgens can freely cross the plasma membrane of target cells and bind to nuclear androgen receptors, inducing gene transcription and protein synthesis. The non-genomic effects have a more rapid onset and may be related to the interaction with protein/receptor/ion channels of the plasma membrane. The key T effect at the vascular level is vasorelaxation, which is primarily due to its rapid effect. Thus, the main purpose of this review is to discuss the T non-genomic effects at the vascular level and the molecular pathways involved in its vasodilator effect observed in in vivo and in vitro studies. In this sense, the nuclear receptor activation, the influence of vascular endothelium and the activation or inhibition of ion channels (potassium and calcium channels, respectively) will be reviewed regarding all the data that corroborated or not. Moreover, this review also provides a brief update on the association of T with the risk factors for cardiovascular diseases, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia, and hypertension. In summary, in this paper we consider the non-genomic vascular mode of action of androgen in physiological conditions and the main risk factors for cardiovascular diseases.


Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Testosterona/farmacología , Animales , Vasos Sanguíneos/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/metabolismo , Humanos , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Receptores Androgénicos/fisiología , Transducción de Señal/efectos de los fármacos , Testosterona/sangre , Vasodilatación/efectos de los fármacos
5.
Can J Urol ; 26(5 Suppl 2): 22-23, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31629421

RESUMEN

Despite significant advances in understanding the biology of advanced prostate cancer and approval of novel therapeutic agents, there is no durable cure for metastatic disease. Recent findings unmasked the importance of androgen receptor (AR) signaling in regulation of DNA repair, and alterations of the AR-DNA repair factor axis were shown to promote aggressive phenotypes including metastasis. These and related findings underscore the importance of determining impact AR-DNA repair factor alterations on prostate cancer progression.


Asunto(s)
Reparación del ADN/fisiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores Androgénicos/fisiología , Humanos , Masculino , Transducción de Señal
6.
DNA Cell Biol ; 38(11): 1323-1337, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31536386

RESUMEN

Our previous study has indicated that the parathyroid hormone type 1 receptor (PTHR1) may play important roles in development and progression of osteosarcoma (OS) by regulating Wnt, angiogenesis, and inflammation pathway genes. The goal of this study was to further illuminate the roles of PTHR1 in OS by investigating upstream regulation mechanisms (including microRNA [miRNA] and transcription factors [TFs]) of crucial genes. The microarray dataset GSE46861 was downloaded from the Gene Expression Omnibus database, in which six tumors with short hairpin RNA (shRNA) PTHR1 knockdown (PTHR1.358) and six tumors with shRNA control knockdown (Ren.1309) were collected from mice. Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the linear models for microarray data (LIMMA) method, and then the miRNA-TF-mRNA regulatory network was constructed using data from corresponding databases, followed by module analysis, to screen crucial regulatory relationships. OS-related human miRNAs were extracted from the curated Osteosarcoma Database. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. As a result, the miRNA-TF-mRNA regulatory network, including 1049 nodes (516 miRNA, 25 TFs, and 508 DEGs) and 15942 edges (interaction relationships, such as Pparg-Abca1 and miR-590-3p-AXIN2), was constructed, from which three significant modules were extracted and modules 2 and 3 contained interactions between miRNAs/TFs and DEGs such as miR-103-3p-AXIN2, miR-124-3p-AR-Tgfb1i1, and miR-27a-3p-PPARG-Abca1. miR-27a-3p was a known miRNA associated with OS. Abca1, AR, and miR-124-3p were hub genes in the miRNA-TF-mRNA network. Tgfb1i1 was involved in cell proliferation, Abca1 participated in the cholesterol metabolic process, and AXIN2 was associated with the canonical Wnt signaling pathway. Furthermore, we also confirmed upregulation of miR-590-3p and downregulation of AXIN2 in the mouse OS cell line K7M2-WT transfected with PTHR1 shRNA. In conclusion, PTHR1 may play important roles in progression of OS by activating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 axes.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Receptor de Hormona Paratiroídea Tipo 1/fisiología , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/fisiología , Animales , Proteína Axina/genética , Proteína Axina/fisiología , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , MicroARNs/fisiología , Osteosarcoma/genética , Osteosarcoma/patología , PPAR gamma/genética , PPAR gamma/fisiología , Receptor de Hormona Paratiroídea Tipo 1/genética , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología , Transducción de Señal/genética , Células Tumorales Cultivadas
7.
J Cancer Res Clin Oncol ; 145(9): 2293-2301, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31401673

RESUMEN

PURPOSE: Androgen receptors (ARs) are expressed on a variety of cell types, and AR signaling plays an important role in tumor development and progression in several cancers. This in vitro study evaluated the effect of dihydrotestosterone (DHT) on the proliferation of renal cell carcinoma (RCC) cells in relation to AR status. METHODS: Steroid hormone receptor expression was evaluated using RT-PCR and Western blotting. The effect of DHT on cell proliferation and STAT5 phosphorylation was evaluated in RCC cell lines (Caki-2, A498, and SN12C) and primary RCC cells using cell viability assays and Western blotting. ARs and glucocorticoid receptors (GRs) were knocked down with small interfering RNAs before assessing changes in cell proliferation and STAT5 activation. RESULTS: DHT treatment promoted cell proliferation and increased STAT5 phosphorylation regardless of AR status. The AR antagonist bicalutamide reduced kidney cancer cell proliferation, regardless of AR status. AR and GR knockdown blocked STAT5 activation and reduced cell proliferation in all RCC cell lines. In patient-derived primary cells, DHT enhanced cell proliferation and this effect was diminished by treatment with the AR antagonists bicalutamide and enzalutamide and the GR antagonist mifepristone. CONCLUSION: DHT promotes cell proliferation through STAT5 activation in RCC cells, regardless of AR status. DHT appears to utilize the AR and GR pathways to activate STAT5, and the inhibition of AR and GR showed antitumor activity in RCC cells. These data suggest that targeting AR and GR may be a promising new approach to the treatment of RCC.


Asunto(s)
Carcinoma de Células Renales/patología , Proliferación Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Neoplasias Renales/patología , Receptores Androgénicos/fisiología , Receptores de Glucocorticoides/fisiología , Factor de Transcripción STAT5/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Factor de Transcripción STAT5/genética , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/genética
8.
Cancer Res ; 79(20): 5260-5271, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31444154

RESUMEN

Loss of expression of context-specific tumor suppressors is a critical event that facilitates the development of prostate cancer. Zinc finger and BTB domain containing transcriptional repressors, such as ZBTB7A and ZBTB16, have been recently identified as tumor suppressors that play important roles in preventing prostate cancer progression. In this study, we used combined ChIP-seq and RNA-seq analyses of prostate cancer cells to identify direct ZBTB7A-repressed genes, which are enriched for transcriptional targets of E2F, and identified that the androgen receptor (AR) played a critical role in the transcriptional suppression of these E2F targets. AR recruitment of the retinoblastoma protein (Rb) was required to strengthen the E2F-Rb transcriptional repression complex. In addition, ZBTB7A was rapidly recruited to the E2F-Rb binding sites by AR and negatively regulated the transcriptional activity of E2F1 on DNA replication genes. Finally, ZBTB7A suppressed the growth of castration-resistant prostate cancer (CRPC) in vitro and in vivo, and overexpression of ZBTB7A acted in synergy with high-dose testosterone treatment to effectively prevent the recurrence of CRPC. Overall, this study provides novel molecular insights of the role of ZBTB7A in CRPC cells and demonstrates globally its critical role in mediating the transcriptional repression activity of AR. SIGNIFICANCE: ZBTB7A is recruited to the E2F-Rb binding sites by AR and negatively regulates the transcriptional activity of E2F1 on DNA replication genes.


Asunto(s)
Adenocarcinoma/genética , Proteínas de Unión al ADN/fisiología , Proteínas de Neoplasias/fisiología , Neoplasias de la Próstata/genética , Receptores Androgénicos/fisiología , Factores de Transcripción/fisiología , Transcripción Genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Sitios de Unión , Línea Celular Tumoral , Replicación del ADN/efectos de los fármacos , Factor de Transcripción E2F1/fisiología , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transporte de Proteínas , Interferencia de ARN , Recurrencia , Proteína de Retinoblastoma/fisiología , Testosterona/farmacología
9.
Sci Rep ; 9(1): 10457, 2019 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-31320667

RESUMEN

Androgens are known to be an essential regulator of male health. Androgen receptor (AR) is widely expressed throughout the adrenal cortex, yet the wider role for androgen signalling in the adrenal remains underexplored. To investigate AR-dependent and AR-independent androgen signalling in the adrenal, we used a novel mouse model with a specific ablation of androgen receptor in the adrenal cortex with or without reduction of circulating androgen levels by castration. Our results describe AR expression in the human and mouse adrenal and highlight that the mouse is a viable model to investigate androgen signalling in the adrenal cortex. We show androgen signalling via AR is required for X-zone regression during puberty. Furthermore, cortex measurements define differences in X-zone morphology depending on whether circulating androgens or AR have been removed. We show androgens promote both cortical cell differentiation and apoptosis but are dispensable for the formation of the definitive cortex. Additionally, investigation of aged mice with AR ablation reveals severe cortex disruption, spindle cell hyperplasia and X-zone expansion. The data described herein demonstrates AR-signalling is required to facilitate X-zone regression, cell clearance and to protect against adrenal degeneration during ageing.


Asunto(s)
Corteza Suprarrenal/citología , Envejecimiento/fisiología , Andrógenos/farmacología , Sustancias Protectoras/farmacología , Receptores Androgénicos/fisiología , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Apoptosis , Castración , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
10.
Oncogene ; 38(38): 6507-6520, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31358900

RESUMEN

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison with mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master regulator analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a coregulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways.


Asunto(s)
Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores Androgénicos/fisiología , Factores de Transcripción SOXB1/fisiología , Proteína p53 Supresora de Tumor/genética , Animales , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Invasividad Neoplásica , Receptores Androgénicos/genética , Transducción de Señal/genética , Transcriptoma
12.
J Clin Invest ; 129(5): 1818-1826, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31042159

RESUMEN

Androgens and estrogens are known to be critical regulators of mammalian physiology and development. While these two classes of steroids share similar structures (in general, estrogens are derived from androgens via the enzyme aromatase), they subserve markedly different functions via their specific receptors. In the past, estrogens such as estradiol were thought to be most important in the regulation of female biology, while androgens such as testosterone and dihydrotestosterone were believed to primarily modulate development and physiology in males. However, the emergence of patients with deficiencies in androgen or estrogen hormone synthesis or actions, as well as the development of animal models that specifically target androgen- or estrogen-mediated signaling pathways, have revealed that estrogens and androgens regulate critical biological and pathological processes in both males and females. In fact, the concept of "male" and "female" hormones is an oversimplification of a complex developmental and biological network of steroid actions that directly impacts many organs. In this Review, we will discuss important roles of estrogens in males and androgens in females.


Asunto(s)
Andrógenos/fisiología , Estrógenos/fisiología , Animales , Huesos/fisiología , Neoplasias de la Mama/patología , Sistema Nervioso Central/fisiología , Dihidrotestosterona , Progresión de la Enfermedad , Estradiol/fisiología , Femenino , Genitales/fisiología , Humanos , Masculino , Ratones , Neoplasias de la Próstata/patología , Receptores Androgénicos/fisiología , Receptores Estrogénicos/fisiología , Factores Sexuales , Testosterona/fisiología
13.
Oncogene ; 38(28): 5700-5724, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31043708

RESUMEN

Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced 'castrate-resistant' disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9 kb 3'UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC therapeutic targets.


Asunto(s)
MicroARNs/fisiología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/fisiología , Regiones no Traducidas 3' , Elementos sin Sentido (Genética) , Línea Celular Tumoral , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Humanos , Masculino , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/patología , Transducción de Señal
14.
Pharmacol Ther ; 200: 135-147, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31077689

RESUMEN

The androgen receptor (AR) is a drug target in breast cancer, and AR-targeted therapies have induced tumor responses in breast cancer patients. In this review, we summarized the role of AR in breast cancer based on preclinical and clinical data. Response to AR-targeted therapies in unselected breast cancer populations is relatively low. Preclinical and clinical data show that AR antagonists might have a role in estrogen receptor (ER)-negative/AR-positive tumors. The prognostic value of AR for patients remains uncertain due to the use of various antibodies and cut-off values for immunohistochemical assessment. To get more insight into the role of AR in breast cancer, we additionally performed a retrospective pooled analysis to determine the prognostic value of the AR using mRNA profiles of 7270 primary breast tumors. Our analysis shows that a higher AR mRNA level is associated with improved disease outcome in patients with ER-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, but with worse disease outcome in HER2-positive subgroups. In conclusion, next to AR expression, incorporation of additional tumor characteristics will potentially make AR targeting a more valuable therapeutic strategy in breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores Androgénicos/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Humanos , Masculino , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , ARN Mensajero/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología
15.
Naunyn Schmiedebergs Arch Pharmacol ; 392(6): 729-742, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30770950

RESUMEN

To study the capability of the CYP17A1 inhibitor abiraterone acetate (AER) to antagonize the androgen receptor (AR) activation in human prostate cancer (PCa) cell lines. T877A-AR-LNCaP, WT-AR-VCaP, AR-negative DU145, and PC3 PCa cell lines were used by MTT and cell count to study the ability of AER and enzalutamide (ENZ) to modify cell viability. The role of ARs in LNCaP was demonstrated through a gene-silencing experiment. The mechanism of AER cytotoxicity in LNCaP cells was studied, as well as the ability of AER to modulate AR gene expression. The in silico docking approach was applied to study the interaction of AER and ENZ with T877A-AR. Through high-performance liquid chromatography, the production of the AER main metabolite Δ4A was studied. AER bound AR in an almost identical manner to that of dihydrotestosterone (DHT). The higher binding energy for AER in T877A-AR could explain the major cytotoxic effect observed in LNCaP cells. The capability of LNCaP cells to synthesize Δ4A could mediate, at least in part, this effect. AER cytotoxicity in LNCaP cells was mainly due to the activation of apoptosis. Further, AER induced modification of AR target gene expression, suggesting a direct effect on AR activity. AER-induced cytotoxicity on PCa cell lines seemed to be mediated by binding with AR. The higher affinity of AER for T877A-AR may suggest a potential role of AER in the management of CRPC carrying this mutation; however, T877A-AR expressing CRPC patients developed AER resistance, probably due to the increase of progesterone.


Asunto(s)
Acetato de Abiraterona/farmacología , Antineoplásicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Acetato de Abiraterona/química , Acetato de Abiraterona/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Humanos , Masculino , Simulación del Acoplamiento Molecular , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/patología , Receptores Androgénicos/química , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología
16.
Artículo en Inglés | MEDLINE | ID: mdl-30291148

RESUMEN

Stem/progenitor cells play central roles in processes of organogenesis and tissue maintenance, whereas cancer stem cells (CSCs) are thought to drive tumor malignancy. Here, we review recent progress in the identification and analysis of normal prostate stem/progenitor cells as well as putative CSCs in both genetically engineered mouse models as well as in human tissue. We also discuss studies that have investigated the cell type of origin for prostate cancer. In addition, we provide a critical assessment of methodologies used in stem cell analyses and outline directions for future research.


Asunto(s)
Células Madre Neoplásicas/patología , Próstata/citología , Neoplasias de la Próstata/patología , Células Madre/citología , Animales , Células Epiteliales/citología , Humanos , Masculino , Ratones , Modelos Biológicos , Receptores Androgénicos/fisiología
17.
Oncogene ; 38(13): 2337-2350, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30510232

RESUMEN

Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor-initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. Here, we directly assessed the essential role of androgen signaling in prostatic p63-expressing cell initiated oncogenic transformation and tumor formation. Using novel and relevant mouse models, we demonstrated that, with stabilized ß-catenin expression, prostatic p63-expressing cells possess the ability to initiate oncogenic transformation and, in the presence of androgens, they further transdifferentiate into luminal-like tumor cells and develop adenocarcinomas. Castration prior to activating stabilized ß-catenin sensitizes p63-expressing cells and increases their sensitivity to androgens, resulting in aggressive and fast growing tumor phenotypes. These findings are consistent with what have been observed in human prostate cancers, demonstrating an essential role for androgen signaling in prostate cancer initiation and progression. This study also provides fresh insight into developing new therapeutic strategies for better treating prostate cancer patients.


Asunto(s)
Andrógenos/fisiología , Transformación Celular Neoplásica , Células Madre Neoplásicas/fisiología , Neoplasias de la Próstata/patología , Andrógenos/metabolismo , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Embrión de Mamíferos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Células Madre Neoplásicas/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células del Estroma/patología , Células del Estroma/fisiología
18.
Horm Behav ; 111: 23-30, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30579744

RESUMEN

For nearly 60 years since the seminal paper from W.C Young and colleagues (Phoenix et al., 1959), the principles of sexual differentiation of the brain and behavior have maintained that female-typical sexual behaviors (e.g., lordosis) and sexual preferences (e.g., attraction to males) are the result of low androgen levels during development, whereas higher androgen levels promote male-typical sexual behaviors (e.g., mounting and thrusting) and preferences (e.g., attraction to females). However, recent reports suggest that the relationship between androgens and male-typical behaviors is not always linear - when androgen signaling is increased in male rodents, via exogenous androgen exposure or androgen receptor overexpression, males continue to exhibit male-typical sexual behaviors, but their sexual preferences are altered such that their interest in same-sex partners is increased. Analogous to this rodent literature, recent findings indicate that high level androgen exposure may contribute to the sexual orientation of a subset of gay men who prefer insertive anal sex and report more male-typical gender traits, whereas gay men who prefer receptive anal sex, and who on average report more gender nonconformity, present with biomarkers suggestive of low androgen exposure. Together, the evidence indicates that for both mice and men there is an inverted-U curvilinear relationship between androgens and sexual preferences, such that low and high androgen exposure increases androphilic sexual attraction, whereas relative mid-range androgen exposure leads to gynephilic attraction. Future directions for studying how individual differences in biological development mediate sexual behavior and sexual preferences in both mice and humans are discussed.


Asunto(s)
Homosexualidad Masculina , Individualidad , Conducta Sexual , Adulto , Andrógenos/metabolismo , Andrógenos/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiología , Femenino , Identidad de Género , Homosexualidad Masculina/psicología , Humanos , Masculino , Ratones , Receptores Androgénicos/fisiología , Diferenciación Sexual/efectos de los fármacos , Diferenciación Sexual/fisiología , Conducta Sexual/fisiología , Conducta Sexual/psicología
19.
Arch Esp Urol ; 71(8): 628-638, 2018 Sep.
Artículo en Español | MEDLINE | ID: mdl-30319123

RESUMEN

The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/etiología , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología
20.
Arch. esp. urol. (Ed. impr.) ; 71(8): 628-638, oct. 2018. graf
Artículo en Español | IBECS | ID: ibc-178741

RESUMEN

El eje de señalización de andrógenos desempeña un papel fundamental en la patogénesis del cáncer de próstata. Desde el descubrimiento histórico de Huggins y Hodges, la depleción androgénica permanece como la piedra angular en el tratamiento de la enfermedad avanzada. Sin embargo, de forma invariable, la progresión a cáncer de próstata resistente a la castración se produce dentro de los 2-3 años posteriores al inicio de la terapia de deprivación androgénica (TDA). Múltiples mecanismos de resistencia ayudan a la progresión a la enfermedad resistente a la castración, y el receptor de andrógenos (RA) sigue siendo un impulsor importante en esta progresión. Los mecanismos moleculares que subyacen a la reactivación del RA en el cáncer de próstata resistente a la castración (CPRC) incluyen la amplificación y sobreexpresión del RA, mutaciones del RA, expresión de variantes constitutivamente activas del RA, síntesis de andrógenos intratumorales y suprarrenales y activación promiscua del RA por otros factores. También se discuten otros mecanismos de resistencia independientes del RA, que incluyen la activación del receptor de glucocorticoides, la alteración de las vías de reparación del ADN, la resistencia mediada por mecanismos inmunes, la diferenciación neuroendocrina y la expresión de microARN. El cáncer de próstata resistente a la castración es una enfermedad compleja, se caracteriza por múltiples mecanismos de resistencia al tratamiento de deprivación de andrógenos, y sigue siendo una enfermedad incurable. La comprensión de los mecanismos que subyacen a esta resistencia es necesaria para identificar objetivos terapéuticos futuros, así como la identificación y validación de nuevos biomarcadores predictivos de resistencia, lo que puede conducir a una mejora terapéutica para pacientes con CPRC


The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients


Asunto(s)
Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/etiología , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología
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