Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.561
Filtrar
1.
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
2.
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
3.
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
4.
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
6.
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
7.
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
8.
Environ Pollut ; 272: 116397, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33433340

RESUMEN

Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and ß-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and ß-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.


Asunto(s)
Andrógenos , Neoplasias de la Próstata , Antagonistas de Andrógenos , Línea Celular Tumoral , Proliferación Celular , Epigénesis Genética , Humanos , Masculino , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
9.
Life Sci ; 269: 119040, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33453241

RESUMEN

AIMS: Low testosterone in men is associated with increased cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors including cholesterol, endothelial dysfunction and inflammation as key mediators of atherosclerosis. Although evidence suggests testosterone is anti-atherogenic, its mechanism of action is unknown. The present study investigates whether testosterone exerts anti-atherogenic effects by stimulating cholesterol clearance from macrophages via activation of liver X receptor (LXRα), a nuclear master regulator of cellular cholesterol homeostasis, lipid regulation, and inflammation. MAIN METHODS: Using human monocyte THP-1 cells differentiated into macrophages, the effect of testosterone (1-10 nM) treatment (24-72 h) on the expression of LXRα and LXR- targets apolipoprotein E (APOE), ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FAS), was investigated via qPCR and western blotting, with or without androgen receptor blockade with flutamide or LXR antagonism with CPPSS-50. Cholesterol clearance was measured by monitoring fluorescent dehydroergosterol (DHE) cellular clearance and ABCA1 cellular translocation was observed via immunocytochemistry in testosterone treated macrophages. KEY FINDINGS: Testosterone increased mRNA and protein expression of LXRα, APOE, ABCA1, SREBF1 and FAS. These effects were blocked by flutamide and independently by LXR antagonism with CPPSS-50. Furthermore testosterone stimulated cholesterol clearance from the macrophages and promoted the translocation of ABCA1 toward the cell membrane. SIGNIFICANCE: Testosterone acts via androgen receptor-dependent pathways to stimulate LXRα and downstream targets to induce cholesterol clearance in human macrophages. This may, in part, explain the anti-atherogenic effects of testosterone frequently seen clinically.


Asunto(s)
Colesterol/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Leucemia Monocítica Aguda/metabolismo , Receptores X del Hígado/metabolismo , Macrófagos/metabolismo , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Andrógenos/farmacología , Humanos , Leucemia Monocítica Aguda/tratamiento farmacológico , Leucemia Monocítica Aguda/patología , Receptores X del Hígado/genética , Macrófagos/efectos de los fármacos , Macrófagos/patología , Receptores Androgénicos/genética , Células Tumorales Cultivadas
10.
Nat Med ; 27(2): 310-320, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33462444

RESUMEN

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.


Asunto(s)
Andrógenos/farmacología , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Receptores Androgénicos/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Femenino , Humanos , Células MCF-7 , Coactivador 3 de Receptor Nuclear/genética , Receptores Androgénicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
11.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451122

RESUMEN

BACKGROUND: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. METHODS: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10-6 M) and bicalutamide (BCT) (10-4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-ß (ERß), respectively. RESULTS: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERß mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. CONCLUSION: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERß expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.


Asunto(s)
Hormonas/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Neoplasias de la Próstata/metabolismo , Transducción de Señal/efectos de los fármacos , Esteroides/metabolismo , Tadalafilo/farmacología , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Transporte de Proteínas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
12.
Oncology ; 99(4): 251-255, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33461196

RESUMEN

BACKGROUND: Androgen receptor splice variant V7 (AR-V7) was recently detected in circulating tumor cells of castration-resistant prostate cancer (PC) patients and its expression correlated with resistance to new-generation androgen signaling inhibitors. OBJECTIVES: We retrospectively analyzed whether AR-V7 expression was detectable on radical prostatectomy (RP) specimens of untreated nonmetastatic PC cases, and whether it could be associated with progression after surgery. METHOD: The expression of AR-V7 and AR-FL (full length) was separately evaluated by immunohistochemistry using a streptavidin-biotin-peroxidase system with 2 anti-AR-V7 and anti-AR-FL rabbit monoclonal antibodies. RESULTS: 56 PC cases, classified by their clinical risk, were analyzed. Positive expression was found in 24/32 cases in the high-risk group, 4/13 in the intermediate-risk group, and only 2/11 in the low-risk group. We found a significant correlation between AR-V7 positivity and both risk classification (p < 0.001) and progression after surgery (p < 0.001). CONCLUSIONS: In our population of untreated nonmetastatic PC, AR-V7 is detectable by immunohistochemistry in more than 50% of cases. At this early stage, AR-V7 positivity is associated with risk classification and it can predict progression after surgery.


Asunto(s)
Progresión de la Enfermedad , Prostatectomía/métodos , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/cirugía , Receptores Androgénicos/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Isoformas de Proteínas/metabolismo , Receptores Androgénicos/genética , Estudios Retrospectivos , Riesgo
13.
Gene ; 772: 145377, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33359129

RESUMEN

AIM: Androgen receptor splice variants (AR-Vs) produced by alternative splicing of the AR play an important role in the treatment resistance and progression of prostate cancer (PCa). In this study, two most common AR variants and how they associate with the inflammatory response (NF-Kß) and regulatory transcriptional activity (HSP-27) genes were investigated in patients with PCa and metastatic PCa (Met-PCa). METHODS: Our study was carried out with the whole blood obtained from 25 healthy control subjects, 25 PCa patients and 39 Met-PCa patients. We examined the expression levels of AR, AR-V7 and AR-V567es genes via Real-time PCR and those of HSP-27 and NF-Kß via ELISA method. RESULTS: AR, AR-V7 and AR-V567es expressions were observed in 84.61%, 64.1%, 23.07% of Met-PCa patients respectively. The expression levels of full-length AR and variants (AR-V7 and AR-V567es) were associated with the prostate cancer stage. In the Met-PCa, the expression levels of AR, AR-V7 and AR-V567es were associated with the Gleason Scores but not with the PSA levels. AR-V7 expression levels in stage T4 patients significantly increased. NF-Kß and HSP-27 protein levels were significantly higher in Met-PCa patients. DISCUSSION: Our findings highlight the targeting of the proteostasis and inflammation pathways through inhibiting HSP-27 and NF-Kß. This might be a valuable strategy to overcome anti-androgen resistance and improve drug therapy in Met-PCa patients whose gene expression levels of AR-V7 and AR-V567es variants are high.


Asunto(s)
Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , FN-kappa B/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Regulación hacia Arriba , Anciano , Empalme Alternativo , Estudios de Casos y Controles , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transducción de Señal
14.
Crit Rev Oncol Hematol ; 157: 103185, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33341506

RESUMEN

In last years several improvements have been made in the management of prostate cancer (PCa). Androgen receptor (AR) is considered the main driver in PCa growth and progression and most drugs are directed against AR pathway. Once PCa spreads outside the prostate, androgen deprivation therapy (ADT) represents the cornerstone of treatment in hormone-sensitive prostate cancer (HSPC). Unfortunately, the response is only transient and most patients eventually develop castration-resistant prostate cancer (CRPC). Most resistance mechanisms depend on maintenance of AR signalling in castration environment. Recent discoveries of multiple growth-promoting and survival pathways in PCa suggest the importance of alternative mechanisms involved in disease progression, such as DNA damage response pathway, PTEN/PI3K/AKT/mTOR pathway, cell cycle pathway, WNT pathway, TMPRSS2/ETS fusion, neuroendocrine pattern and immune system response. In this review, we discuss the interplay between AR signaling and other molecular pathways involved in PCa pathogenesis and their therapeutic implication in advanced disease.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Antagonistas de Andrógenos , Progresión de la Enfermedad , Humanos , Masculino , Fosfatidilinositol 3-Quinasas , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética
15.
Arch Oral Biol ; 122: 105026, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33348207

RESUMEN

OBJECTIVE: This study evaluated the gene expression and protein synthesis of sex hormone receptors in human periodontal ligament cells (PDLCs) in relation to donor- and tooth-specific factors with the aim to clarify the debate about sex hormone receptors in PDLCs. DESIGN: The expression patterns of estrogen receptors (genes: ESR1 and ESR2; proteins: ERα and ERß), androgen receptor (AR) and progesterone receptor (PR) were investigated in the context of immortalization status, previous orthodontic tooth movement (OTM), donor age, sex and hormonal stimulation in PDLCs from 14 healthy donors (male: n = 8, female: n = 6; adolescents: n = 8, adults: n = 6) using quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. RESULTS: For ERß, the full-length isoform ERß1 and truncated variants were detected. For ERα, the expected isoform ERα66 was not observed, but a novel isoform ERα36 was detected. Immortalization status, previous OTM and donor age had no impact on ESR1 and ESR2 expression. Estradiol stimulation for 24 h doubled the ratio of ESR2/ESR1 in PDLCs from female but not male donors, indicating sex-specific patterns of receptor expression. AR and PR demonstrated insufficient protein synthesis in PDLCs. CONCLUSIONS: The data revealed a pivotal role for and complex interplay between ERα and ERß in human PDLCs regardless of variable donor characteristics. Therefore, PDLC biology might be altered in patients of each age group and both sexes due to hormonal changes. This should be kept in mind during periodontic and orthodontic treatment of patients with special hormonal status.


Asunto(s)
Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Ligamento Periodontal/citología , Receptores Androgénicos/genética , Receptores de Progesterona/genética , Adolescente , Adulto , Estradiol , Femenino , Humanos , Masculino , Factores Sexuales , Donantes de Tejidos
16.
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
17.
Nat Genet ; 52(10): 1011-1017, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32868907

RESUMEN

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.


Asunto(s)
Factor Nuclear 3-alfa del Hepatocito/genética , Histona Demetilasas/genética , Neoplasias de la Próstata/genética , Unión Proteica/genética , Antagonistas de Receptores Androgénicos/farmacología , Animales , Línea Celular Tumoral , Cromatina/genética , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Hormonas Esteroides Gonadales/genética , Xenoinjertos , Humanos , Masculino , Ratones , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética
18.
Am J Pathol ; 190(11): 2194-2202, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32805234

RESUMEN

The prostate epithelium consists of predominantly luminal cells that express androgen receptor and require androgens for growth. As a consequence, the depletion of testicular androgens in patients with prostate cancer results in tumor regression. However, it eventually leads to a castration-resistant disease that is highly metastatic. In this report, a mouse model of metastatic prostate cancer was generated through the deletion of the tumor-suppressor gene Trp53 in conjunction with oncogenic activation of the proto-oncogene Kras. These mice developed early-onset metastatic prostate cancer with complete penetrance. Tumors from these mice were poorly differentiated adenocarcinoma, characterized by extensive epithelial-mesenchymal transition. With no or a very low level of androgen receptor expression, the tumor cells were resistant to androgen receptor inhibition. Pik3cg, encoding phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (Pi3kγ), was highly expressed in these tumors, and pharmacologic inhibition of Pi3kγ blocked tumor cell growth in vitro, reversed epithelial-mesenchymal transition, and abated tumor metastasis in vivo. Immunohistochemistry analysis in human prostate cancer specimens showed that the expression of PIK3CG was significantly associated with advanced clinical stages. Taken together, these results suggest that PIK3CG plays an important role in the progression and metastasis of prostate cancer, and may represent a new therapeutic target in the metastatic castration-resistant prostate cancer.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Animales , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Masculino , Ratones , Ratones Transgénicos , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética
19.
Arch Biochem Biophys ; 692: 108521, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32800775

RESUMEN

Diabetic cardiac fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Cardiac fibroblast autophagy plays critical roles in diabetic cardiac fibrosis, however, the underlying mechanism of cardiac fibroblast autophagy and diabetic cardiac fibrosis still largely unknown. The aim of the study was to investigate the mechanism of DNMT1 mediated DNA methylation alterations control cardiac fibroblast autophagy in diabetic cardiac fibrosis. We employed streptozotocin (STZ)-induced rats DCM, DCM patient and Hcy induced cardiac fibroblast autophagy. Heart tissue sections were stained with H&E, Sirius Red and Masson's trichrome stain. The expression of DNMT1, AR, Collagen genes mRNA was detected by qRT-PCR. MSP and BSP detected the methylation status of the AR promoter. The expression of DNMT1, AR, Collagen and autophagy-related proteins were detected by Western blotting, Immunofluorescence, Immunohistochemistry. Gain and loss function of AR and DNMT1 in cardiac fibroblast was analyzed. DNMT1 inhibition or knockdown elevated the expression of AR in cardiac fibroblast. Furthermore, we found that AR negatively regulation of Hcy induced cardiac fibroblast autophagy. We demonstrated that DNMT1 enhances cardiac fibroblast autophagy in diabetic cardiac fibrosis through inhibiting AR axis. In conclusion, our results provide new insight into the DNMT1 inactivation of AR axis triggers cardiac fibroblast autophagy in diabetic cardiac fibrosis.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1 , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Inhibidores Enzimáticos/farmacología , Fibroblastos/metabolismo , Homocisteína/metabolismo , Miocardio/metabolismo , Receptores Androgénicos , Animales , Colágeno/biosíntesis , Colágeno/genética , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Fibroblastos/patología , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Homocisteína/genética , Masculino , Miocardio/patología , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
20.
Nat Commun ; 11(1): 4153, 2020 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-32814769

RESUMEN

The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.


Asunto(s)
N-Metiltransferasa de Histona-Lisina/genética , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-myc/genética , Receptores Androgénicos/genética , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Línea Celular Tumoral , Supervivencia sin Enfermedad , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Compuestos de Fenilurea/farmacología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Estabilidad Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Tratamiento con ARN de Interferencia/métodos , Receptores Androgénicos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...