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1.
Nat Commun ; 12(1): 1117, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602919

RESUMEN

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.


Asunto(s)
Modelos Biológicos , Organoides/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Andrógenos/metabolismo , Antineoplásicos/uso terapéutico , Genoma Humano , Humanos , Masculino , Mutación/genética , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Transcriptoma/genética
2.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33466491

RESUMEN

Androgens represent the main hormones responsible for maintaining hormonal balance and function in the prostate and testis. As they are involved in prostate and testicular carcinogenesis, more detailed information of their active concentration at the site of action is required. Since the introduction of the term intracrinology as the local formation of active steroid hormones from inactive precursors of the adrenal gland, mainly dehydroepiandrosterone (DHEA) and DHEA-S, it is evident that blood circulating levels of sex steroid hormones need not reflect their actual concentrations in the tissue. Here, we review and critically evaluate available methods for the analysis of human intraprostatic and intratesticular steroid concentrations. Since analytical approaches have much in common in both tissues, we discuss them together. Preanalytical steps, including various techniques for separation of the analytes, are compared, followed by the end-point measurement. Advantages and disadvantages of chromatography-mass spectrometry (LC-MS, GC-MS), immunoanalytical methods (IA), and hybrid (LC-IA) are discussed. Finally, the clinical information value of the determined steroid hormones is evaluated concerning differentiating between patients with cancer or benign hyperplasia and between patients with different degrees of infertility. Adrenal-derived 11-oxygenated androgens are mentioned as perspective prognostic markers for these purposes.


Asunto(s)
Glándulas Suprarrenales/metabolismo , Andrógenos/metabolismo , Próstata/metabolismo , Testículo/metabolismo , Animales , Hormonas Esteroides Gonadales/metabolismo , Humanos , Masculino , Esteroides/metabolismo
3.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503805

RESUMEN

Castration-resistant prostate cancer (CRPC) is an advanced and androgen-independent form of prostate cancer. Recent studies of rapid actions mediated by estrogen in the prostate and its relationship with CRPC are emerging. We have previously shown that estrogen receptor (ER) promotes migration and invasion of the androgen-independent prostate cancer cells PC-3, but the signaling pathways involved in these events remain to be elucidated. Therefore, this study aimed to analyze the role of ERα and ERß in the activation of SRC, and the involvement of SRC and PI3K/AKT on invasion and colony formation of the PC-3 cells. Our results showed that the activation of ERα (using ERα-selective agonist PPT) and ERß (using ERß-selective agonist DPN) increased phosphorylation of SRC in PC-3 cells. In the presence of the selective inhibitor for SRC-family kinases PP2, the effects of DPN and PPT on transmigration and soft agar colony formation assays were decreased. Furthermore, SRC is involved in the expression of the non-phosphorylated ß-catenin. Finally, using PI3K specific inhibitor Wortmannin and AKT inhibitor MK2206, we showed that PI3K/AKT are also required for invasion and colony formation of PC-3 cells simulated by ER. This study provides novel insights into molecular mechanisms of ER in PC-3 cells by demonstrating that ER, located outside the cell nucleus, activates rapid responses molecules, including SRC and PI3K/AKT, which enhance the tumorigenic potential of prostate cancer cells, increasing cell proliferation, migration, invasion, and tumor formation.


Asunto(s)
Andrógenos/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Estrogénicos/metabolismo , Transducción de Señal , Línea Celular Tumoral , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Humanos , Inmunohistoquímica , Masculino , Células PC-3 , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismo , Familia-src Quinasas/metabolismo
4.
Eur J Endocrinol ; 184(3): 353-363, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33444228

RESUMEN

Objective: Androgens are important modulators of immune cell function. The local generation of active androgens from circulating precursors is an important mediator of androgen action in peripheral target cells or tissues. We aimed to characterize the activation of classic and 11-oxygenated androgens in human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were isolated from healthy male donors and incubated ex vivo with precursors and active androgens of the classic and 11-oxygenated androgen pathways. Steroids were quantified by liquid chromatography-tandem mass spectrometry. The expression of genes encoding steroid-metabolizing enzymes was assessed by quantitative PCR. Results: PBMCs generated eight-fold higher amounts of the active 11-oxygenated androgen 11-ketotestosterone than the classic androgen testosterone from their respective precursors. We identified the enzyme AKR1C3 as the major reductive 17ß-hydroxysteroid dehydrogenase in PBMCs responsible for both conversions and found that within the PBMC compartment natural killer cells are the major site of AKRC13 expression and activity. Steroid 5α-reductase type 1 catalyzed the 5α-reduction of classic but not 11-oxygenated androgens in PBMCs. Lag time prior to the separation of cellular components from whole blood increased serum 11-ketotestosterone concentrations in a time-dependent fashion, with significant increases detected from two hours after blood collection. Conclusions: 11-Oxygenated androgens are the preferred substrates for androgen activation by AKR1C3 in PBMCs, primarily conveyed by natural killer cell AKR1C3 activity, yielding 11-ketotestosterone the major active androgen in PBMCs. Androgen metabolism by PBMCs can affect the results of serum 11-ketotestosterone measurements, if samples are not separated in a timely fashion. Significance statement: We show that human peripheral blood mononuclear cells (PBMCs) preferentially activate 11-ketotestosterone rather than testosterone when incubated with precursors of both the classic and the adrenal-derived 11-oxygenated androgen biosynthesis pathways. We demonstrate that this activity is catalyzed by the enzyme AKR1C3, which we found to primarily reside in natural killer cells, major contributors to the anti-viral immune defense. This potentially links intracrine 11-oxygenated androgen generation to the previously observed decreased NK cell cytotoxicity and increased infection risk in primary adrenal insufficiency. In addition, we show that PBMCs continue to generate 11-ketotestosterone if the cellular component of whole blood samples is not removed in a timely fashion, which could affect measurements of this active androgen in routine clinical biochemistry.


Asunto(s)
Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Andrógenos/metabolismo , Leucocitos Mononucleares/metabolismo , Cromatografía Liquida , Humanos , Masculino , Espectrometría de Masas en Tándem , Testosterona/análogos & derivados , Testosterona/metabolismo
5.
Am J Physiol Renal Physiol ; 320(2): F243-F248, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33464168

RESUMEN

Coronavirus disease 2019 (COVID-19) has reached pandemic proportions, affecting millions of people worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19. Epidemiological reports have shown that the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, all of which are also risk factors for acute kidney injury (AKI). The kidney has emerged as a key organ affected by SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with COVID-19. Male sex is an independent predictor for AKI, and an increased death rate has been reported in male patients with COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain(s) unknown. Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been implicated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-angiotensin system, impair renal hemodynamics, predisposing patients to AKI during COVID-19 infection, which could explain the higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of the role of androgens in SARS-CoV-2-associated AKI and mortality is imperative. The kidney could constitute a key organ that may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.


Asunto(s)
Lesión Renal Aguda/virología , Andrógenos/metabolismo , /patología , Riñón/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Síndrome del Ovario Poliquístico , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Factores Sexuales , Personas Transgénero , Investigación en Medicina Traslacional
6.
Ecotoxicol Environ Saf ; 208: 111566, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396095

RESUMEN

Androgens and estrogens often co-exist in aquatic environments and pose potential risks to fish populations. However, little is known about the endocrine disrupting effects of the mixture of androgens and estrogens in fish. In this study, transcriptional level of target genes related to the hypothalamic-pituitary-gonadal-liver (HPGL) axis, sex hormone level, VTG protein concentration, histology and secondary sex characteristic were assessed in the ovaries and livers of adult female western mosquitofish (Gambusia affinis) exposed to 17ß-estradiol (E2), testosterone (T), and mixtures of E2 and T for 91 days. The results showed that the transcriptional expression of cytochrome P450, family 19, subfamily A, polypeptide 1a (Cyp19a1a) was suppressed in the 200 ng/L T treatment and the 50 ng/L E2 + 200 ng/L T treatment in the ovaries. Steroidogenic acute regulatory protein (Star) and Cyp11a1 showed a similar expression pattern in the T treatment to its corresponding T + E2 mixtures. In the ovaries, the concentrations of 17ß-estradiol and testosterone were decreased in most treatments compared with the solvent control. VTG protein was induced in all steroid treatment. However, exposure to T or E2 + T mixture did not cause the abnormal cells of the ovaries and livers and an extension of the anal fins in female G. affinis. This study demonstrates that chronic exposure to E2, T and their mixtures affects the transcripts of genes in the HPGL axis, steroid hormone level and VTG protein concentration in the ovaries and livers, but fails to cause the histopathological effect of the ovaries and livers and alter the morphology of the anal fins in G. affinis.


Asunto(s)
Ciprinodontiformes/fisiología , Disruptores Endocrinos/toxicidad , Estradiol/toxicidad , Andrógenos/metabolismo , Animales , Ciprinodontiformes/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Disruptores Endocrinos/metabolismo , Estradiol/metabolismo , Estrógenos/metabolismo , Femenino , Hormonas Esteroides Gonadales/metabolismo , Hígado/efectos de los fármacos , Masculino , Ovario/efectos de los fármacos , Testosterona/metabolismo , Vitelogeninas/metabolismo
7.
Nat Commun ; 12(1): 401, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33452241

RESUMEN

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.


Asunto(s)
Carcinogénesis/genética , Criptocromos/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación/genética , Anciano , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Andrógenos/metabolismo , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Criptocromos/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Estudios de Seguimiento , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , RNA-Seq , Receptores Androgénicos/metabolismo , Reparación del ADN por Recombinación/efectos de los fármacos , Estudios Retrospectivos
8.
Methods Mol Biol ; 2264: 187-196, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33263911

RESUMEN

Homozygous lines occur for plant breeding programs and for studies about gene expression and genetic mapping and they can be derived from anther culture. In this chapter, the method to obtain androgenic plants from an ornamental cut flower, Anemone coronaria belonging to the Ranunculaceae family, is described. In this species, androgenic plants were obtained culturing anthers with responsive microspores in Petri dishes containing a double layer of substrate with specific composition. Moreover, thermic treatment has been applied to induce the switch from pollen development program to embryo development program. The method allows to produce both double-haploid plants from diploid mothers (2n) and di-haploid plants from tetraploid mothers (4n).


Asunto(s)
Andrógenos/metabolismo , Anemone/crecimiento & desarrollo , Flores/crecimiento & desarrollo , Fitomejoramiento/métodos , Ploidias , Polen/crecimiento & desarrollo , Anemone/genética , Anemone/metabolismo , Flores/genética , Flores/metabolismo , Polen/genética , Polen/metabolismo
9.
Adv Exp Med Biol ; 1270: 169-183, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33123999

RESUMEN

The key function of mesenchymal/stromal androgen receptor (AR) signaling for prostate development has been well documented by tissue recombination experiments. Some studies have addressed the expression and function of AR in stromal cells in prostate cancer, yet our understanding of the role of stromal AR in other tissues beyond prostate is still insufficient.Genomic analysis has revealed that cellular responses to androgens differ between epithelial and stromal cells. AR in stromal cells seems not to act via classical AR transcription factors such as FOXA1 but rather depends on the JUN/AP1 complex. Stromal AR appears to have tumor-promoting and tumor-protective functions depending on tumor stage. Loss of AR signaling in fibroblasts has been detected already in premalignant lesions in the skin and prostate and has been associated with tumor induction in xenografts of skin cancer and aggressive disease features and poor patient prognosis in prostate cancer. Moreover, AR expression is found on virtually all tissue-infiltrating immune cells and plays critical roles in immune cell function. These findings suggest a potential deleterious impact of current androgen deprivation therapies which inhibit both epithelial and stromal AR, highlighting the need to develop tissue-specific AR inhibitors.


Asunto(s)
Andrógenos/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Microambiente Tumoral , Antagonistas de Andrógenos , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico
10.
Nutrients ; 12(12)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33333818

RESUMEN

The purpose of this study was (1) to determine the effect of single bouts of volume- and intensity-equated low- (LL) and high-load (HL) full-body resistance exercise (RE) on AR-DNA binding, serum/muscle testosterone and dihydrotestosterone, muscle androgen receptor (AR), and AR-DNA binding; and, (2) to determine the effect of RE on sarcoplasmic and nucleoplasmic ß-catenin concentrations in order to determine their impact on mediating AR-DNA binding in the absence/presence of serum/muscle androgen and AR protein. In a cross-over design, 10 resistance-trained males completed volume- and intensity-equated LL and HL full-body RE. Blood and muscle samples were collected at pre-, 3 h-, and 24 h post-exercise. Separate 2 × 3 factorial analyses of variance (ANOVAs) with repeated measures and pairwise comparisons with a Bonferroni adjustment were used to analyze the main effects. No significant differences were observed in muscle AR, testosterone, dihydrotestosterone, or serum total testosterone in either condition (p > 0.05). Serum-free testosterone was significantly decreased 3 h post-exercise and remained significantly less than baseline 24 h post-exercise in both conditions (p < 0.05). In response to HL, AR-DNA binding significantly increased at 3 h post-exercise (p < 0.05), whereas no significant differences were observed at any time in response to LL (p > 0.05). Moreover, sarcoplasmic ß-catenin was significantly greater in HL (p < 0.05) without significant changes in nucleoplasmic ß-catenin (p > 0.05). In conclusion, increases in AR-DNA binding in response to HL RE indicate AR signaling may be load-dependent. Furthermore, despite the lack of increase in serum and muscle androgens or AR content following HL RE, elevations in AR-DNA binding with elevated sarcoplasmic ß-catenin suggests ß-catenin may be facilitating this response.


Asunto(s)
Andrógenos/metabolismo , Ejercicio Físico/fisiología , Receptores Androgénicos/metabolismo , Entrenamiento de Resistencia/métodos , Vía de Señalización Wnt/fisiología , Adolescente , Adulto , Análisis de Varianza , Análisis Factorial , Voluntarios Sanos , Humanos , Masculino , Músculo Esquelético/metabolismo , Unión Proteica/fisiología , Testosterona/metabolismo , Adulto Joven , beta Catenina/metabolismo
11.
PLoS One ; 15(12): e0242970, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33326447

RESUMEN

Chronic inflammation promotes prostate cancer (PCa) initiation and progression. We previously reported that acute intereluekin-1 (IL-1) exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR-independent PCa cells. We generated isogenic sublines from LNCaP cells chronically exposed to IL-1α or IL-1ß. Cells were treated with IL-1α, IL-1ß, TNFα or HS-5 bone marrow stromal cells conditioned medium to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and enzalutamide treatment. Finally, RNA sequencing was performed for the IL-1 sublines. MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation-induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA-mediated loss of AR, serum deprivation and enzalutamide. Differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.


Asunto(s)
Andrógenos/metabolismo , Interleucina-1/farmacología , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Masculino , Subunidad p50 de NF-kappa B/metabolismo , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacología
12.
PLoS One ; 15(12): e0243277, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33332371

RESUMEN

Understanding the reproductive biology of the roan antelope (Hippotragus equinus) (É. Geoffroy Saint-Hilaire, 1803) is crucial to optimise breeding success in captive breeding programmes of this threatened species. In this study, the pattern of faecal androgen metabolite (fAM) production related to reproductive events (calving or birthing, mating, gestation, and lactation), sexual behaviours as well as environmental cues were studied in captive adult male roan antelope. Faecal sample collection and behavioural observations were carried out from August 2017 to July 2018 for three reproductive males participating in a conservation breeding programme at the Lapalala Wilderness Nature Reserve in South Africa. As a prerequisite, the enzyme immunoassay used in this study was biologically validated for the species by demonstrating a significant difference between fAM concentrations in non-breeding adults, breeding adults and juvenile males. Results revealed that in adults males, the overall mean fAM levels were 73% higher during the breeding period compared to the non-breeding periods, and 85% higher when exclusively compared to the lactation/gestation periods, but only 5.3% higher when compared to the birthing period. Simultaneously, fAM concentrations were lower during the wet season compared to the dry season, increasing with a reduction in photoperiod. With the exception of courtship, frequencies of sexual behaviours monitored changed in accordance with individual mean fAM concentrations in male roan antelope, the findings suggest that androgen production varies with the occurrence of mating activity and may be influenced by photoperiod but not with rainfall.


Asunto(s)
Andrógenos/metabolismo , Antílopes/fisiología , Andrógenos/análisis , Animales , Heces/química , Femenino , Masculino , Reproducción , Estaciones del Año
13.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33334082

RESUMEN

Cornus officinalis, widely used in traditional Chinese medicine, exhibits pharmacological effects against erectile dysfunction and pollakisuria, which are pathological symptoms of benign prostatic hyperplasia (BPH). Although traditional usage and a study on BPH have been reported, to our knowledge, no study has investigated the exact molecular mechanism(s) underlying the anti-proliferative effects of standardized C. officinalis on prostatic cells. We standardized C. officinalis 30% ethanol extract (COFE) and demonstrated the therapeutic effects of COFE on human BPH epithelial cells and testosterone-induced BPH in rats. In vitro studies using BPH-1 cells demonstrated an upregulation of BPH-related and E2F Transcription Factor 1(E2F1)-dependent cell cycle markers, whereas treatment with COFE clearly inhibited the proliferation of BPH epithelial cells and reduced the overexpression of G1 and S checkpoint genes. Additionally, COFE administration alleviated the androgen-dependent prostatic enlargement in a testosterone-induced BPH animal model. COFE exerted these anti-BPH effects by the inhibition of anti-apoptotic markers, suppression of PCNA expression, and regulation of E2F1/pRB-dependent cell cycle markers in rats with BPH. These results suggest that COFE exerts anti-proliferative effect by regulating PCNA/E2F1-dependent cell cycle signaling pathway both in vivo and in vitro. These findings reveal the therapeutic potential of COFE, which could be used as a substitute for BPH treatment.


Asunto(s)
Cornus/química , Factor de Transcripción E2F1/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Extractos Vegetales/farmacología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Próstata/metabolismo , Andrógenos/metabolismo , Animales , Biomarcadores , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Humanos , Masculino , Extractos Vegetales/química , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/etiología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Ratas , Transducción de Señal/efectos de los fármacos , Testosterona/metabolismo , Testosterona/farmacología
14.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-33318251

RESUMEN

Leydig cell tumours (LCTs) of the ovary are rare ovarian tumours that usually present with hyperandrogenism. Conventional radiological imagings are helpful in localising these tumours. However, some tumours may be too small to be localised before curative surgical removal. It is important to identify these androgen-secreting neoplasms which originate mostly from adrenals or ovaries because they are potentially malignant and require specific treatment. When conventional imagings are unrevealing, selective ovarian and adrenal venous sampling (SOAVS) is the next option. We report a case of LCT that was localised by SOAVS after results from other imaging modalities remained inconclusive.


Asunto(s)
Hiperandrogenismo/etiología , Tumor de Células de Leydig/complicaciones , Tumor de Células de Leydig/patología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/patología , Adulto , Andrógenos/metabolismo , Femenino , Hirsutismo/etiología , Humanos , Laparoscopía , Tumor de Células de Leydig/metabolismo , Tumor de Células de Leydig/cirugía , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/cirugía , Salpingooforectomía
15.
Radiol Clin North Am ; 58(6): 1099-1113, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33040851

RESUMEN

Endocrine disorders associated with adrenal pathologies can be caused by insufficient adrenal gland function or excess hormone secretion. Excess hormone secretion may result from adrenal hyperplasia or hormone-secreting (ie, functioning) adrenal masses. Based on the hormone type, functioning adrenal masses can be classified as cortisol-producing tumors, aldosterone producing tumors, and androgen-producing tumors, which originate in the adrenal cortex, as well as catecholamine-producing pheochromocytomas, which originate in the medulla. Nonfunctioning lesions can cause adrenal gland enlargement without causing hormonal imbalance. Evaluation of adrenal-related endocrine disorders requires clinical and biochemical workup associated with imaging evaluation to reach a diagnosis and guide management.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Síndrome de Cushing/diagnóstico por imagen , Enfermedades del Sistema Endocrino/diagnóstico por imagen , Feocromocitoma/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Adrenalectomía/métodos , Aldosterona/metabolismo , Andrógenos/metabolismo , Síndrome de Cushing/patología , Enfermedades del Sistema Endocrino/fisiopatología , Femenino , Humanos , Hidrocortisona/metabolismo , Masculino , Feocromocitoma/patología , Pronóstico , Índice de Severidad de la Enfermedad
17.
Nat Commun ; 11(1): 4822, 2020 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-32973149

RESUMEN

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents.


Asunto(s)
Acetato de Abiraterona/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Verrucomicrobia/efectos de los fármacos , Acetato de Abiraterona/metabolismo , Acetato de Abiraterona/uso terapéutico , Antagonistas de Andrógenos/farmacología , Andrógenos/metabolismo , Bacterias/metabolismo , Heces/microbiología , Humanos , Masculino , ARN Ribosómico 16S/genética , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Vitamina K 2/metabolismo , Vitamina K 2/farmacología
18.
PLoS One ; 15(9): e0226056, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32881870

RESUMEN

The androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating that they may play a role in development of Prostate Cancer (PCa) and CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. By using blast analysis of 826 GPCRs, we identified a GPCR, GPCR 205, which exhibited maximum similarity with the ligand binding domain of the AR. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all twenty-five prostate tumor patient's samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.


Asunto(s)
Andrógenos/metabolismo , Núcleo Celular/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anciano , Animales , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Simulación del Acoplamiento Molecular , Próstata/citología , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/cirugía , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Testosterona/metabolismo , Transcripción Genética
19.
Aquat Toxicol ; 227: 105586, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32882451

RESUMEN

Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.


Asunto(s)
Andrógenos/toxicidad , Dihidrotestosterona/toxicidad , Estrógenos/metabolismo , Hepatocitos/efectos de los fármacos , Testosterona/toxicidad , Trucha/metabolismo , Contaminantes Químicos del Agua/toxicidad , Andrógenos/metabolismo , Animales , Células Cultivadas , Dihidrotestosterona/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Estrógenos/genética , Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Masculino , Cultivo Primario de Células , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Testosterona/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Contaminantes Químicos del Agua/metabolismo
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