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

RESUMEN

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


Asunto(s)
Proteína NEDD8/genética , Neoplasias de la Próstata/genética , Procesamiento Proteico-Postraduccional , Proteínas Quinasas Asociadas a Fase-S/genética , Factores de Transcripción de la Familia Snail/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclopentanos/farmacología , Docetaxel/farmacología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Proteína NEDD8/metabolismo , Clasificación del Tumor , Células PC-3 , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo
2.
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
3.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672769

RESUMEN

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


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Proteolisis/efectos de los fármacos
4.
Nat Med ; 27(3): 426-433, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664492

RESUMEN

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


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Transcripción Genética/efectos de los fármacos , Biopsia , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo
5.
Eur J Med Chem ; 216: 113307, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652354

RESUMEN

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


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Proteolisis , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/genética , Relación Estructura-Actividad , Tasa de Supervivencia , Trasplante Heterólogo , Pez Cebra/crecimiento & desarrollo , Pez Cebra/fisiología
6.
Eur J Med Chem ; 216: 113247, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652355

RESUMEN

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


Asunto(s)
Proteínas Inhibidoras de la Apoptosis/metabolismo , Ligandos , Antineoplásicos/química , Antineoplásicos/metabolismo , Proteínas Fetales/antagonistas & inhibidores , Proteínas Fetales/metabolismo , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Proteína Huntingtina/antagonistas & inhibidores , Proteína Huntingtina/metabolismo , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/metabolismo , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Receptores Estrogénicos/metabolismo
7.
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
8.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

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


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Biol Res ; 54(1): 3, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33546773

RESUMEN

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Glucosa/metabolismo , Miocitos Cardíacos , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Cultivadas , Hipertrofia , Masculino , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Transducción de Señal
10.
Nat Commun ; 12(1): 734, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531470

RESUMEN

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.


Asunto(s)
Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/metabolismo , Regulador Transcripcional ERG/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Ratones , Ratones Desnudos , Mutación/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Neoplasias de la Próstata/genética , Unión Proteica , Proteómica , Receptores Androgénicos/metabolismo , Proteínas Represoras/genética , Transducción de Señal/fisiología , Regulador Transcripcional ERG/genética , Complejos de Ubiquitina-Proteína Ligasa/genética
11.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546359

RESUMEN

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


Asunto(s)
Conducta Materna , Periodo Posparto , Área Preóptica/metabolismo , Receptores Androgénicos/fisiología , Animales , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Madres , Ratas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Secuencia de ARN
12.
Ecotoxicol Environ Saf ; 214: 112086, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33640727

RESUMEN

Production of polychlorinated biphenyls (PCBs) was banned a long time ago because of their harmful health effects but humans continue to be exposed to residual PCBs in the environment. In this study, the susceptibility of human nuclear receptors to binding by PCBs was investigated using molecular docking simulation. Findings revealed that PCBs belonging to ortho-substituted, mono-ortho-substituted and non-ortho-substituted congeners could bind to agonistic conformations of androgen (AR), estrogen (ER α and ER ß), glucocorticoid (GR) and thyroid hormone (TR α and TR ß) receptors as well as antagonistic conformation of androgen receptor (AR an) but only ortho-substituted and mono-ortho-substituted PCBs could bind to estrogen receptors in their antagonistic conformations (ER α an and ER ß an). Further molecular docking analyses showed that PCBs mimic the modes of interaction observed for the co-crystallized ligands in the crystal structures of the affected receptors, utilizing 81%, 83%, 78%, 60%, 75%, 60%, 86%, 100% and 75% of the amino acid residues utilized by the co-crystallized ligands for binding in AR, AR an, ER α, ER α an, ER ß, ER ß an, GR, TR α and TR ß respectively. This computational study suggests that PCBs may cause endocrine disruption via formation of non-covalent interactions with androgen, estrogen, glucocorticoid and thyroid hormone receptors.


Asunto(s)
Disruptores Endocrinos/toxicidad , Bifenilos Policlorados/toxicidad , Andrógenos , Disruptores Endocrinos/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno , Humanos , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Simulación del Acoplamiento Molecular , Bifenilos Policlorados/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas
13.
Cell Transplant ; 30: 963689721991477, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33522308

RESUMEN

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/complicaciones , Antagonistas de Estrógenos/uso terapéutico , Neoplasias de la Próstata/complicaciones , Tamoxifeno/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , /metabolismo , Descubrimiento de Drogas , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/análisis , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/análisis , Serina Endopeptidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacología
14.
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
15.
Biochem Biophys Res Commun ; 537: 78-84, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33387886

RESUMEN

The prostate cancer (PCa) poses serious threat to men's health. The androgen receptor (AR) is essential for normal prostate development and prostate cancer progression. We identified a novel lncRNA PCLN16 which is significantly correlated with AR signaling during prostate cancer progression. The AR-regulated PCLN16 was abundantly overexpressed in localized or metastatic prostate cancer tissues and AR-dependent cell lines. PCLN16 silence suppressed AR signaling and tumor growth. PCLN16 interacted with Huntingtin interacting protein 1 (HIP1) transcript to reduce HIP1 degradation. Therefore, PCLN16 could augment AR signaling via a novel positive feedback loop. Our experiments support an oncogenic role for PCLN16 and suggest that PCLN16 might serve as a potential target for therapeutic intervention.


Asunto(s)
Neoplasias de la Próstata/genética , ARN Largo no Codificante/metabolismo , Receptores Androgénicos/genética , Transducción de Señal , Secuencia de Bases , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Masculino , Neoplasias de la Próstata/patología , Estabilidad del ARN/genética , ARN Largo no Codificante/genética , Receptores Androgénicos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
16.
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
17.
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
18.
Int J Nanomedicine ; 16: 315-327, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33469288

RESUMEN

Background: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined. Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression. Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation. Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.


Asunto(s)
Andrógenos/farmacología , Exosomas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba/efectos de los fármacos , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Exosomas/ultraestructura , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Microambiente Tumoral
19.
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
20.
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
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