Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.761
Filtrar
1.
Urol Clin North Am ; 48(3): 339-347, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210489

RESUMO

Androgen receptor function, tumor cell plasticity, loss of tumor suppressors, and defects in DNA repair genes affect aggressive features of prostate cancer. Prostate cancer development, progression, and aggressive behavior are often attributable to function of the androgen receptor. Tumor cell plasticity, neuroendocrine features, and loss of tumor suppressors lend aggressive behavior to prostate cancer cells. DNA repair defects have ramifications for prostate cancer cell behavior.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Antagonistas de Androgênios/uso terapêutico , Biomarcadores Tumorais/genética , Plasticidade Celular , Reparo do DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Masculino , Medicina de Precisão , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia
2.
Nat Commun ; 12(1): 3372, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099734

RESUMO

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.


Assuntos
Adenocarcinoma/genética , Carcinoma Neuroendócrino/genética , Regulação Neoplásica da Expressão Gênica , Próstata/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Adenocarcinoma/metabolismo , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Técnicas de Cultura de Órgãos/métodos , Prognóstico , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
6.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073713

RESUMO

Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.


Assuntos
Mutação , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Processamento Alternativo , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Humanos , Masculino , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/genética , Isoformas de Proteínas
7.
Crit Rev Oncol Hematol ; 163: 103370, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34051300

RESUMO

Prostate cancer (PC) is the most frequently diagnosed cancer and the second leading cause of cancer-related death in men in the Western society. Unfortunately, although the vast majority of patients are initially responsive to androgen-deprivation therapy (ADT), most cases eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). The main reason is PC heterogeneity and evolution during therapy. PC evolution is a continuously progressive process with combination of genomic alterations including canonical AR, TMPRSS2-ERG fusion, SPOP/FOXA1, TP53/RB1/PTEN, BRCA2. Meanwhile, signaling pathways including PI3K, WNT/ß-catenin, SRC, IL-6/STAT3 are activated, to promote epithelial mesenchymal transition (EMT), cancer stem cell (CSC)-like features/stemness and neuroendocrine differentiation (NED) of PC. These improve our understanding of the genotype-phenotype relationships. The identification of canonical genetic alterations and signaling pathway activation in PC has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios , Transição Epitelial-Mesenquimal/genética , Genótipo , Humanos , Masculino , Proteínas Nucleares , Fenótipo , Receptores Androgênicos/genética , Proteínas Repressoras
8.
Nat Commun ; 12(1): 2705, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976187

RESUMO

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/genética , Processamento de Proteína Pós-Traducional , Receptores Androgênicos/genética , ADP-Ribosilação/efeitos dos fármacos , Adenocarcinoma , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , Metribolona/farmacologia , Proteínas de Neoplasias/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise de Sobrevida
9.
Zhonghua Fu Chan Ke Za Zhi ; 56(4): 251-256, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33902236

RESUMO

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


Assuntos
Síndrome de Resistência a Andrógenos , Síndrome de Resistência a Andrógenos/diagnóstico , Síndrome de Resistência a Andrógenos/genética , Feminino , Aconselhamento Genético , Humanos , Masculino , Projetos Piloto , Gravidez , Diagnóstico Pré-Natal , Receptores Androgênicos/genética , Estudos Retrospectivos
10.
Cancer Res ; 81(4): 1087-1100, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33822745

RESUMO

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.


Assuntos
Histona Desmetilases com o Domínio Jumonji/fisiologia , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Processamento Alternativo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Terapia de Alvo Molecular , Oxigenases/genética , Oxigenases/fisiologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Estudos Retrospectivos
11.
Ann Oncol ; 32(6): 726-735, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33794293

RESUMO

BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. PATIENTS AND METHODS: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). RESULTS: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. CONCLUSIONS: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona , Biomarcadores Tumorais/genética , Conversão Gênica , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Resultado do Tratamento
12.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799604

RESUMO

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.


Assuntos
Proteína NEDD8/genética , Neoplasias da Próstata/genética , Processamento de Proteína Pós-Traducional , Proteínas Quinases Associadas a Fase S/genética , Fatores de Transcrição da Família Snail/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ciclopentanos/farmacologia , Docetaxel/farmacologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Proteína NEDD8/metabolismo , Gradação de Tumores , Células PC-3 , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/metabolismo , Fatores de Transcrição da Família Snail/metabolismo
13.
Med Hypotheses ; 150: 110566, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33799157

RESUMO

Currently, the biggest challenge for prostate cancer (PCa) is to understand the mechanism by which the disease acquires the castration-resistant phenotype and progresses to a fatal disease. PCa has a high genetic heterogeneity, and cannot be separated into well-defined molecular subtypes. Despite this, there is consensus about the role of the androgen receptor (AR) in all stages of the disease, including the transition to the castration-resistant phenotype. Since AR is a transcription factor, we investigated the possibility of PCa presenting a pattern of global gene expression during disease progression. By analyzing the TCGA and CCLE datasets, we were able to find a pattern of waves of genes being expressed during each stage of disease progression. This phenomenon suggests the existence of a mechanism that globally regulates gene expression, being AR, telomeres, and zinc finger proteins (ZNF), three important players. The AR modulates the telomere biology, and its transcription is regulated by ZNF. Recently, a study suggested that the telomere length might influence the expression of ZNF. Thus, we hypothesized that changes in the triad AR, telomeres, and ZNF control gene expression during the progression of PCa.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Telômero/genética , Telômero/metabolismo , Dedos de Zinco
14.
Int J Mol Sci ; 22(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801338

RESUMO

The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Bibliotecas de Moléculas Pequenas/farmacologia , Transcrição Genética , Antagonistas de Receptores de Andrógenos/química , Simulação por Computador , DNA de Neoplasias/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Conformação Proteica , Domínios Proteicos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Bibliotecas de Moléculas Pequenas/química , Células Tumorais Cultivadas
15.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652992

RESUMO

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.


Assuntos
Aprendizado Profundo , Ligação Proteica/genética , Proteínas/genética , Receptores Androgênicos/genética , Algoritmos , Animais , Humanos , Ligantes , Modelos Logísticos , Redes Neurais de Computação , Ratos , Software
16.
J Food Biochem ; 45(4): e13702, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33694182

RESUMO

The aim of this study was to investigate the anti-androgenic effects of astaxanthin (AST) on human prostatic cancer cell growth, and its impact on androgen receptor (AR) signaling using prostate cancer (PCa) cell line LNCaP. LNCaP cells were treated with AST alone and in combination with CH223191 and flutamide (Flu) in the presence and absence of testosterone. MTT assay, cellular prostate-specific antigen (PSA) and dihydrotestosterone (DHT) production, mRNA levels of CYP1A1, PSA, Kallikrein-Related Peptidase 2 (KLK2), Transmembrane Serine Protease 2 (TMPRSS2), and AR genes were measured as endpoints. The expression of CYP1A1, PSA, KLK2, TMPRSS2, and AR mRNA levels was decreased which results in reducing the production of PSA and DHT in the presence of testosterone. Our data clearly demonstrate that AST has a potential ability to suppress the human prostate LNCaP cells growth at high concentrations. AST was able to repress the testosterone-induced transcription of AR-target genes. PRACTICAL APPLICATIONS: Astaxanthin is a natural compound with the most potent antioxidant activity among other antioxidants. In the current study, ASX suppressed the LNCaP cells at high concentrations. Furthermore, AST inhibited testosterone-induced transcriptional activation of androgen-related genes. AST induced the expression of CYP1A1, which is able to metabolize the steroid hormones. It seems that AST can act as AhR exogenous ligand by induction of CYP1A1, which results in testosterone metabolism and consequent suppression of AR genes. So that, AST could prevent the growth of testosterone-dependent PCa cells, downregulate downstream genes in testosterone pathways, and enhance the metabolism of testosterone via AhR pathway. Collectively, AST could be considered as a potential candidate for the treatment of PCa.


Assuntos
Antagonistas de Androgênios , Androgênios , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , Receptores Androgênicos/genética , Receptores de Hidrocarboneto Arílico , Xantofilas/farmacologia
17.
J Urol ; 206(2): 279-288, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33780283

RESUMO

PURPOSE: We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing. MATERIALS AND METHODS: A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers. RESULTS: We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence of PTEN alteration was found in viscerally metastatic prostate cancer compared with bone-only metastatic prostate cancer (PTEN, 9.09% vs 2.08%, p=0.105). When comparing viscerally metastatic prostate cancer according to the metastatic sites, AR alteration rarely occurs in hepatically metastatic prostate cancer, which stood in great contrast to the high alteration frequency in hepatically metastatic prostate cancer (0.0% vs 42.1%, p=0.01). For overall DNA damage response alteration, the highest frequency was found in hepatically metastatic prostate cancer (63.2%). CONCLUSIONS: Through genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of AR alterations in pulmonarily metastatic prostate cancer without liver involvement, high prevalence of DNA damage response pathway deficiency in hepatically metastatic prostate cancer and high PTEN alteration rates in viscerally metastatic prostate cancer. We discovered the genomic diversity among bone-only metastatic prostate cancer, hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint at potential therapeutic targets in both hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement.


Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Proteína BRCA2/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Quinases Ciclina-Dependentes/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Receptores Androgênicos/genética , Proteínas de Ligação a Retinoblastoma/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
18.
Eur J Med Chem ; 217: 113376, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33756125

RESUMO

Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/síntese química , Flavonoides/química , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
EBioMedicine ; 65: 103246, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33647767

RESUMO

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.


Assuntos
COVID-19/patologia , Peptídeos/genética , Receptores Androgênicos/genética , Idoso , Estudos de Casos e Controles , Cuidados Críticos/estatística & dados numéricos , Feminino , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Espanha , Testosterona/sangue
20.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658518

RESUMO

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.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulação Neoplásica da Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Masculino , Inclusão em Parafina , Fenótipo , Receptor de Morte Celular Programada 1/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Análise Serial de Tecidos , Transcriptoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...