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1.
Anticancer Res ; 39(11): 5879-5890, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704812

RESUMO

BACKGROUND/AIM: The aim of the study was to investigate the prognostic role of androgen receptor (AR), mineralocorticoid receptor (MR) and glucocorticoid receptor ß (GRß) expression in HER-2 negative breast cancer patients. MATERIALS AND METHODS: The study population (n=152) was enriched with triple-negative breast cancers (TNBC) (n=96; 63.2%). The median follow-up time was 100 months. AR, MR and GRß immunocytochemical staining was compared with that of epithelial-mesenchymal transition (EMT) markers (vimentin, SIP1, ZEB1). RESULTS: High expression of cytoplasmic MR was associated with dismal local relapse-free survival (RR=13.923; 95%CI=1.071-181.045; p=0.044) in tumours with non-TNBC phenotype. AR and GRß were more frequently expressed in ER+/PR+/HER2- tumours, while cytoplasmic MR was more often expressed in TNBC tumours (for all, p<0.0005). GRß and AR were associated with decreased vimentin expression (p<0.005), indicating their association with attenuated EMT. CONCLUSION: Cytoplasmic MR expression is a strong predictor of local recurrence in non-metastatic breast cancer patients with non-TNBC tumour phenotype.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Neoplasias da Mama/mortalidade , Citoplasma/metabolismo , Recidiva Local de Neoplasia/mortalidade , Receptores de Mineralocorticoides/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
2.
J Chem Theory Comput ; 15(11): 6504-6512, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31584802

RESUMO

We present an explicit solvent alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38, and the androgen receptor. The sets of optimized charges can be used to identify design principles for chemical changes to the ligands which improve the binding affinity for all three systems. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement for the beneficial mutations of approximately 1 kcal/mol. In the cases where experimental data are available, the agreement between prediction and experiment is also good. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulfur mutations.


Assuntos
Fator Xa/química , Ligantes , Receptores Androgênicos/química , Proteínas Quinases p38 Ativadas por Mitógeno/química , Sítios de Ligação , Fator Xa/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Receptores Androgênicos/metabolismo , Eletricidade Estática , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Life Sci ; 234: 116768, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445027

RESUMO

In prostate cancer development, the androgen receptor (AR) signaling plays a crucial role during both formation of early prostate lesions and progression to the lethal, incurable castration resistant stage. Accordingly, numerous approaches have been developed to inhibit AR activity including androgen deprivation therapy, application of the AR antagonists as well as the use of taxanes. However, these treatments, although effective initially, resistance inevitably occur for most of the patients within several years and limiting the therapeutic efficacy. Of note, alterations and reactivation of the AR signaling pathway have been demonstrated as the major reasons for the observed resistance. Accumulating evidences have suggested that synthesis of AR splicing variants, in particular, the constitutively active AR-V7, is one of the most important mechanisms that contribute to the abnormal AR signaling. In addition, clinical data also highlight the potential of using AR-V7 as a predictive biomarker and a therapeutic target in metastatic castration resistant prostate cancer (mCRPC). In this review, we summarize the recent findings concerning the specific role of AR-V7 in CRPC progression, drug resistance and its potential value in clinical assessment.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Taxoides/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
4.
Eur J Med Chem ; 182: 111608, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437779

RESUMO

Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Pirazóis/farmacologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Pirazóis/síntese química , Pirazóis/química , Receptores Androgênicos/genética , Relação Estrutura-Atividade
5.
Cancer Sci ; 110(11): 3476-3485, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454442

RESUMO

Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)-interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration-resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR-positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1-target genes, disks large-associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non-SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer-specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.


Assuntos
Proteínas de Ciclo Celular/genética , Cinesina/genética , Proteínas de Neoplasias/genética , Fator 1 de Transcrição de Octâmero/fisiologia , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , Análise em Microsséries , Proteínas Nucleares/genética , Fator 1 de Transcrição de Octâmero/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Receptores Androgênicos/metabolismo , Taxa de Sobrevida , Regulação para Cima
6.
Eur J Med Chem ; 179: 660-666, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279298

RESUMO

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 µM on LNCaP (AR+) in comparison to 13.3 µM on PC3 (AR-) and 8.8 µM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 µM, 0.5 µM and 1.0 µM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 µM. This is not the case for CDDP showing IC50 of 1.3 µM and 5.1 µM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Testosterona/química
7.
Tumour Biol ; 41(7): 1010428318824815, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31296150

RESUMO

GATA2 is a pioneering transcription factor governing androgen receptor expression and signaling in prostate cells. To understand the prognostic potential of GATA2 assessment in prostate cancer, we analyzed nuclear GATA2 expression on an annotated tissue microarray with 12,427 prostate cancer samples. Normal prostate glands were negative to weakly positive. GATA2 staining was found in almost all prostate cancers (95%). Strong GATA2 staining was linked to advanced tumor stage, high classical and quantitative Gleason grade (p < 0.0001 each), positive nodal stage (p = 0.0116), and early biochemical recurrence (p < 0.0001). GATA2 was linked to ERG-fusion-type cancers, with strong GATA2 staining in 29% of ERG-negative and 53% of ERG-positive cancers (p < 0.0001). Separate calculations in 3854 cancers with and 4768 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. GATA2 expression was further linked to androgen receptor expression: Only 8% of androgen receptor-negative, but 56% of strongly androgen receptor expressing cancers had strong GATA2 expression (p < 0.0001). In conclusion, the results of our study demonstrate that increasing GATA2 levels are linked to prostate cancer progression and aggressiveness. The prognostic value of GATA2 is remarkable in ERG-negative cancers. However, the upregulation of GATA2 in ERG-positive cancers makes it unsuitable as a prognostic marker in this patient subset.


Assuntos
Fator de Transcrição GATA2/metabolismo , Neoplasias da Próstata/metabolismo , Adulto , Idoso , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Recidiva Local de Neoplasia , Fenótipo , Prognóstico , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Análise Serial de Tecidos , Regulador Transcricional ERG/metabolismo , Resultado do Tratamento
8.
Cell Physiol Biochem ; 53(1): 215-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31299143

RESUMO

BACKGROUND/AIMS: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. METHODS: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca2+ ([Ca2+]i) measured using Fluo-3 loaded real time [Ca2+]i imaging. RESULTS: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca2+]i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca2+ influx via L-type channels and store-operated Ca2+ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. CONCLUSION: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca2+]i towards alleviating airway hyperresponsiveness.


Assuntos
Cálcio/metabolismo , Receptores Androgênicos/metabolismo , Asma/metabolismo , Asma/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interleucina-13/farmacologia , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/genética , Fatores Sexuais , Molécula 1 de Interação Estromal/metabolismo , Testosterona/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
9.
Eur J Med Chem ; 178: 168-176, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181481

RESUMO

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/síntese química , Esteroides/metabolismo , Fatores de Transcrição/metabolismo
10.
BMC Bioinformatics ; 20(1): 356, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238876

RESUMO

BACKGROUND: Breast and prostate cancers are typical examples of hormone-dependent cancers, showing remarkable similarities at the hormone-related signaling pathways level, and exhibiting a high tropism to bone. While the identification of genes playing a specific role in each cancer type brings invaluable insights for gene therapy research by targeting disease-specific cell functions not accounted so far, identifying a common gene signature to breast and prostate cancers could unravel new targets to tackle shared hormone-dependent disease features, like bone relapse. This would potentially allow the development of new targeted therapies directed to genes regulating both cancer types, with a consequent positive impact in cancer management and health economics. RESULTS: We address the challenge of extracting gene signatures from transcriptomic data of prostate adenocarcinoma (PRAD) and breast invasive carcinoma (BRCA) samples, particularly estrogen positive (ER+), and androgen positive (AR+) triple-negative breast cancer (TNBC), using sparse logistic regression. The introduction of gene network information based on the distances between BRCA and PRAD correlation matrices is investigated, through the proposed twin networks recovery (twiner) penalty, as a strategy to ensure similarly correlated gene features in two diseases to be less penalized during the feature selection procedure. CONCLUSIONS: Our analysis led to the identification of genes that show a similar correlation pattern in BRCA and PRAD transcriptomic data, and are selected as key players in the classification of breast and prostate samples into ER+ BRCA/AR+ TNBC/PRAD tumor and normal tissues, and also associated with survival time distributions. The results obtained are supported by the literature and are expected to unveil the similarities between the diseases, disclose common disease biomarkers, and help in the definition of new strategies for more effective therapies.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/genética , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Estrogênios/metabolismo , Feminino , Redes Reguladoras de Genes , Humanos , Modelos Logísticos , Masculino , Análise de Componente Principal , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
11.
Nature ; 571(7765): 413-418, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243372

RESUMO

ABTRACT: Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9-11 and oncogenic12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/genética , Mutação/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Fator 3-alfa Nuclear de Hepatócito/química , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Modelos Moleculares , Metástase Neoplásica/genética , Domínios Proteicos , Receptores Androgênicos/metabolismo , Via de Sinalização Wnt
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(5): 419-424, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31223111

RESUMO

Objective To investigate the effects of leucine-rich pentatricopeptide repeat containing (LRPPRC) on proliferation and apoptosis in hormone resistant prostate cancer cells. Methods LRPPRC and androgen receptor (AR) expressions in DU145 and LNCaP cells were detected by Western blot analysis. The siRNA targeting LRPPRC gene was transiently transfected into DU145 cells. LRPPRC expression was detected by reverse transcription PCR and Western blot analysis. The cell survival rate was analyzed by MTT assay. ATP was measured by luciferin-luciferase assay. The cell apoptosis was investigated by flow cytometry and Hoechst 33258 staining. Caspase-3, Bcl2 and BAX protein expressions were detected by Western blot analysis. Results DU145 and LNCaP cells highly expressed LRPPRC. LNCaP cells highly expressed AR, while no expression of AR was observed in DU145 cells. Down-regulation of LRPPRC decreased cell survival rate and ATP level, increased apoptosis rate and caspase-3 activation, and decreased Bcl2 expression in DU145 cells. Conclusion Knock-down of LRPPRC promotes apoptosis of hormone resistant prostate cancer cells.


Assuntos
Apoptose , Proteínas de Neoplasias/genética , Neoplasias da Próstata/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Androgênicos/metabolismo
13.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151151

RESUMO

Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (p < 0.001, p < 0.001, respectively) and it correlated with ER expression (R = 0.630, R = 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01, p < 0.001), and AR low tumors enriched DNA repair (NES = -2.02, p < 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Receptores Androgênicos/genética , Receptores Estrogênicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Reparo do DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia Neoadjuvante , Prognóstico , RNA Mensageiro , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/genética , Resultado do Tratamento
14.
Int J Mol Sci ; 20(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151315

RESUMO

Sex steroids, including androgens, estrogens, and progestogens, are known to have widespread physiological actions beyond the reproductive system via binding to the sex hormone receptors, members of the nuclear receptor superfamily that function as ligand-inducible transcription factors [...].


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Neoplasias/metabolismo , Receptores de Esteroides/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Receptores Androgênicos/metabolismo
15.
Res Vet Sci ; 125: 170-175, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31247472

RESUMO

X-chromosome inactivation pattern (XCIP) analysis can be used to assess the clonality of cell populations of various origin by distinguishing the methylated X chromosome from the unmethylated X chromosome. In this study, the utility of XCIP analysis was improved by incorporating the examination of AC dinucleotide repeats in SLIT and NTRK-like family member 4 (SLITRK4) gene into the previously reported CAG repeat examination of androgen receptor (AR) gene in dogs. The rate of heterozygosity when both genes were analysed (125/150, 83.3%) was higher than AR gene examination alone (86/150, 57.3%). Blood samples from heterozygous dogs in either AC-1 or AC-2 of SLITRK4 gene were examined for the corrected inactivation allele ratio (CIAR), resulting in the determination of a reference range of CIAR <3.8 in non-neoplastic cell/tissue samples. Using this analytical method, 49% (21/43) of neoplastic tissue samples from dogs showed a CIAR >3.8, indicating the presence of a clonal population. Through the present study, the availability of canine XCIP analysis was improved by incorporating the examination of the SLITRK4 gene, providing a highly useful laboratory examination system for the detection of the clonality of various cell/tissue samples in dogs.


Assuntos
Proteínas de Membrana/metabolismo , Receptores Androgênicos/metabolismo , Inativação do Cromossomo X , Cromossomo X/fisiologia , Alelos , Animais , Linhagem da Célula , Doenças do Cão/genética , Doenças do Cão/metabolismo , Cães , Feminino , Regulação da Expressão Gênica , Heterozigoto , Masculino , Proteínas de Membrana/genética , Neoplasias/genética , Neoplasias/metabolismo , Receptores Androgênicos/genética
16.
Chem Soc Rev ; 48(13): 3497-3512, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31214680

RESUMO

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.


Assuntos
Boranos/química , Animais , Boranos/farmacologia , Desenho de Drogas , Enzimas/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fator 1 Induzível por Hipóxia/metabolismo , Ligantes , Receptores Androgênicos/metabolismo , Receptores de Calcitriol/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Purinérgicos/metabolismo
17.
Methods Mol Biol ; 1966: 107-124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041742

RESUMO

ADP-ribosylation is a posttranslational modification generated by members of the superfamily of ADP-ribosyltransferases, known as the Parp enzymes. Depending on the superfamily member, Parp enzymes can mono- or poly-ADP-ribosylate a protein substrate. Parp superfamily members confer regulation to a variety of biological processes that include cell signaling, DNA repair, transcription, and stress responses. Here, we describe biochemical methods for detection of ADP-ribose conjugated to the androgen receptor (AR) using the archaeal macrodomain, AF1521, from Archaeoglobus fulgidus. The utility of AF1521 is based on its highly selective recognition of ADP-ribose conjugated to protein. AF1521 immobilized on beads can be used to enrich for ADP-ribosylated proteins, which in our application results in recovery of ADP-ribosylated AR from prostate cancer cell extracts. We engineered tandem AF1521 macrodomains and found this improves the recovery of ADP-ribosylated AR under native conditions, and it enabled development of an assay for detection of ADP-ribosylation on blots. Thus, AF1521 can be used to query ADP-ribosylation of protein under both native and denaturing conditions. Our assays should prove useful for understanding how ADP-ribosylation regulates AR function.


Assuntos
ADP-Ribosilação , Técnicas In Vitro/métodos , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/análise , Receptores Androgênicos/metabolismo , Adenosina Difosfato Ribose/análise , Proteínas Arqueais , Archaeoglobus fulgidus/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino
18.
Hum Cell ; 32(3): 379-389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119584

RESUMO

Men are at a higher risk of developing bladder cancer than women. Although the urinary bladder is not regarded as an sex organ, it has the potential to respond to androgen signals. The mechanisms responsible for the gender differences remain unexplained. Androgen receptor (AR) after binding with 5α-dihydrotestosteron (DHT) undergoes a conformational change and translocates to nucleus to induce transcriptional regulation of target genes. However androgen/AR signaling can also be activated by interacting with several signaling molecules and exert its non-genomic function. The aim of present study was to explain whether the progression of bladder cancer in men is dependent on androgen/AR signaling. Studies were carried out on human bladder cancer cell lines: HCV29, T24, HT1376 and HTB9. Bladder cancer cells were treated for 48 h with 10 nM DHT or not, with replacement after 24 h. Expression of cell signaling proteins, was analyzed using Western Blot and RT-PCR. Subcellular localization of protein was studied using the ProteoExtract Subcellular Proteome Extraction Kit and Western blot analysis. We showed that DHT treatment significantly increased AR expression in bladder cell line HCV29. We also observed DHT-mediated activation of Akt/GSK-3ß signaling pathway which plays a central role in cancer progression. Presented results also show that androgen/AR signaling is implicated in phosphorylation of eIF4E which can promote epithelial-mesenchymal transition (EMT). We indicate that AR plays an essential role in bladder cancer progression in male patients. Therefore, androgen-activated AR signaling is an attractive regulatory target for the inhibition or prevention of bladder cancer incidence in men.


Assuntos
Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/genética , Células Cultivadas , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Terapia de Alvo Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Risco , Caracteres Sexuais , Transdução de Sinais/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia
19.
Molecules ; 24(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052610

RESUMO

BACKGROUND: The aim of this study was to simplify and identify the contents of the herbal formula, HBX-5. This study was carried out to evaluate the therapeutic effects of HBX-6 in a mouse model of benign prostatic hyperplasia (BPH). Based on in vitro, we selected a candidate, reconstituted an experimental agent and investigated the effects on testosterone-induced BPH rats. Cell viability was determined by MTT assay in RWPE-1 and WPMY-1 cells. The expression of androgen receptor (AR) was measured in dihydrotestosterone-stimulated RWPE-1 and WPMY-1 cells. BPH was induced in mice by a subcutaneous injection of testosterone propionate for four weeks. Animals were divided into six groups: Group 1, control mice; Group 2, mice with BPH; Group 3, mice with BPH treated with finasteride; Group 4, mice with BPH treated with 200 mg/kg HBX-5; Group 5, mice with BPH treated with 100 mg/kg HBX-6; and Group 6, mice with BPH treated with 200 mg/kg HBX-6. Changes in prostate weight were measured after treatments, and the thickness of the epithelium was evaluated. The expression levels of proteins associated with prostatic cell proliferation and cell cycle-related proteins were determined. Based on previous reports and in vitro results, we selected Cornus officinalis and Psoralea corylifolia among HBX-5 components and reconstituted the experimental agent, and named it HBX-6. The result represented a new herbal formula, HBX-6 that suppressed the pathological alterations in BPH and showed a marked reduction in proliferation-related protein expression compared to mice with BPH. Our results indicate that HBX-6 has a better therapeutic effect in the BPH murine model than those of HBX-5 and finasteride, suggesting the role of HBX-6 as a new BPH remedial agent.


Assuntos
Cornus/química , Fator de Transcrição E2F1/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/metabolismo , Psoralea/química , Animais , Ciclo Celular , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
20.
Food Chem Toxicol ; 130: 199-206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128219

RESUMO

Mycotoxins in food may threat public health at a global scale. However, for most of them, the current body of knowledge does not support a proper risk assessment and more data are needed to clarify their toxicity. In particular, the assessment of "personalized" action may succeed in understanding and counteracting the effects of many toxicants. Therefore, the assessment of "personalized" toxicology of mycotoxins might deserve attention to foster the understanding of their mechanisms of toxicity and to eventually improve the assessment of risk. This work dealt with the early warning analysis of possible differences in eliciting androgenic stimuli by alternariol, a widespread mycotoxin produce by Alternaria species, when mutations on the androgen receptor occur. It was applied a computational study based on docking simulations, pharmacophore modeling and molecular dynamics to assess the capability of alternariol to interact with the androgen receptor bearing the M749I substitution - which confers insensitivity to androgens stimulation. The results collected pointed to possible "protective" effects against alternariol suggesting: i) the likely existence of inter-individual responses to alternariol stimulation; ii) the meaningfulness of collecting data on "personalized" response to mycotoxins toward a more precise paradigm addressing the risk assessment at the individual level.


Assuntos
Contaminação de Alimentos , Inocuidade dos Alimentos , Lactonas/toxicidade , Simulação de Dinâmica Molecular , Humanos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Esteroides/química , Esteroides/metabolismo
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