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[PMID]:28324044
[Au] Autor:Audet-Walsh É; Yee T; Tam IS; Giguère V
[Ad] Endereço:Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
[Ti] Título:Inverse Regulation of DHT Synthesis Enzymes 5α-Reductase Types 1 and 2 by the Androgen Receptor in Prostate Cancer.
[So] Source:Endocrinology;158(4):1015-1021, 2017 Apr 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2.
[Mh] Termos MeSH primário: 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
Proteínas de Membrana/metabolismo
Próstata/metabolismo
Neoplasias da Próstata/metabolismo
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Androgênios/farmacologia
Linhagem Celular Tumoral
Progressão da Doença
Seres Humanos
Calicreínas/metabolismo
Masculino
Metribolona/farmacologia
Próstata/efeitos dos fármacos
Próstata/patologia
Antígeno Prostático Específico/metabolismo
Neoplasias da Próstata/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Membrane Proteins); 0 (Receptors, Androgen); 2C323EGI97 (Metribolone); EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase); EC 1.3.99.5 (SRD5A1 protein, human); EC 1.3.99.5 (SRD5A2 protein, human); EC 3.4.21.- (Kallikreins); EC 3.4.21.- (kallikrein-related peptidase 3, human); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1926


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[PMID]:27426262
[Au] Autor:Huang PH; Wang HY; Huang CC; Lee YT; Yue CH; Chen MC; Lin H
[Ad] Endereço:Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
[Ti] Título:Suppression of breast cancer cell growth by Her2-reduced AR serine 81 phosphorylation.
[So] Source:Chin J Physiol;59(4):232-9, 2016 Aug 31.
[Is] ISSN:0304-4920
[Cp] País de publicação:China (Republic : 1949- )
[La] Idioma:eng
[Ab] Resumo:Breast cancer is a hormone-related carcinoma and the most commonly diagnosed malignancy in women. Although Her-2, estrogen receptor (ER), and progesterone receptor (PR) are the major diagnostic markers and therapeutic targets to breast cancer, searching for additional molecular targets remains an important issue and one of the candidates is androgen receptor (AR). AR has been shown expressed in 70% breast cancer patients and connects to low recurrence and high survival rate. Our previous study demonstrates that Ser81 phosphorylation of AR in prostate cancer cells is critical for its protein stability modulated by human epidermal growth factor receptor-2 (Her2). The aim of this study is to investigate the influence of Her2 and AR in proliferation of breast cancer cell line, MDA-MB-453. The data show that AR which was activated by synthetic androgen R1881 suppressed the proliferation of MDA-MB-453 cells. Notably, AR activation decreased the protein levels of cell growth-related proteins, including cyclin A, cyclin B, and early growth response protein 1 (Egr1), while cell-cycle inhibitor protein p27 was increased. Besides, Heregulin (HRG)-induced Her2 activation decreased the AR protein levels and its Ser81 phosphorylation. Her2 small molecular inhibitor, Lapatinib, dose-dependently suppressed cell proliferation while the levels of phospho-Ser81 AR and p27 protein were increased. Phospho-Ser81 AR was also increased after Her2 knockdown. Specifically, the influence of phospho-Ser81 AR by Lapatinib was primarily found in the nucleus of MDA-MD-453 cells, where the cell proliferation might directly be interfered. In conclusion, our findings indicate that Her2 might negatively regulate AR phosphorylation/activation and contribute to regulate the proliferation of MDA-MB 453 cells.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Proliferação Celular
Receptor ErbB-2/metabolismo
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Linhagem Celular Tumoral
Seres Humanos
Metribolona
Terapia de Alvo Molecular
Fosforilação
Quinazolinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Quinazolines); 0 (Receptors, Androgen); 0VUA21238F (lapatinib); 2C323EGI97 (Metribolone); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170622
[Lr] Data última revisão:
170622
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:26786102
[Au] Autor:Shankar E; Song K; Corum SL; Bane KL; Wang H; Kao HY; Danielpour D
[Ad] Endereço:Division of General Medical Sciences-Oncology.
[Ti] Título:A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells.
[So] Source:J Biol Chem;291(11):5512-26, 2016 Mar 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The transcription factor c-Fos controls many important cellular processes, including cell growth and apoptosis. c-Fos expression is rapidly elevated in the prostate upon castration-mediated androgen withdrawal through an undefined mechanism. Here we show that androgens (5α-dihydrotestosterone and R1881) suppress c-Fos protein and mRNA expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) or EGF in human prostate cancer (PCa) cell lines. Such suppression transpires through a transcriptional mechanism, predominantly at the proximal serum response element of the c-fos promoter. We show that androgen signaling suppresses TPA-induced c-Fos expression through repressing a PKC/MEK/ERK/ELK-1 signaling pathway. Moreover, our results support the hypothesis that p38(MAPK), PI3K, and PKCδ are involved in the androgenic regulation of c-Fos through controlling MEK/ERK. Stable silencing of c-Fos and PKCδ with shRNAs suggests that R1881 promotes cell death induced by low-dose TPA through a mechanism that is dependent on both PKCδ and loss of c-Fos expression. Reciprocally, loss of either PKCδ or c-Fos activates p38(MAPK) while suppressing the activation of ERK1/2. We also provide the first demonstration that R1881 permits cell death induced by low-dose TPA in the LNCaP androgen-dependent PCa cell line and that TPA-induced cell death is independent of exogenous androgen in the castration-resistant variants of LNCaP, C4-2 and C4-2B. Acquisition of androgen-independent killing by TPA correlates with activation of p38(MAPK), suppression of ERK1/2, and loss of c-Fos. These results provide new insights into androgenic control of c-Fos and use of PKC inhibitors in PCa therapy.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Androgênios/farmacologia
Di-Hidrotestosterona/farmacologia
Metribolona/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Proteínas Proto-Oncogênicas c-fos/genética
Acetato de Tetradecanoilforbol/farmacologia
[Mh] Termos MeSH secundário: Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Morte Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Regulação para Baixo/efeitos dos fármacos
Fator de Crescimento Epidérmico/farmacologia
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
Próstata/efeitos dos fármacos
Próstata/metabolismo
Próstata/patologia
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Proteína Quinase C/metabolismo
RNA Mensageiro/genética
Transdução de Sinais/efeitos dos fármacos
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Androgens); 0 (Proto-Oncogene Proteins c-fos); 0 (RNA, Messenger); 08J2K08A3Y (Dihydrotestosterone); 2C323EGI97 (Metribolone); 62229-50-9 (Epidermal Growth Factor); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170311
[Lr] Data última revisão:
170311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160121
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.694877


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[PMID]:26039262
[Au] Autor:Chinta G; Ramya Chandar Charles M; Klopcic I; Sollner Dolenc M; Periyasamy L; Selvaraj Coumar M
[Ad] Endereço:Interdisciplinary Program in Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
[Ti] Título:In Silico and In Vitro Investigation of the Piperine's Male Contraceptive Effect: Docking and Molecular Dynamics Simulation Studies in Androgen-Binding Protein and Androgen Receptor.
[So] Source:Planta Med;81(10):804-12, 2015 Jul.
[Is] ISSN:1439-0221
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Understanding the molecular mechanism of action of traditional medicines is an important step towards developing marketable drugs from them. Piperine, an active constituent present in the Piper species, is used extensively in Ayurvedic medicines (practiced on the Indian subcontinent). Among others, piperine is known to possess a male contraceptive effect; however, the molecular mechanism of action for this effect is not very clear. In this regard, detailed docking and molecular dynamics simulation studies of piperine with the androgen-binding protein and androgen receptors were carried out. Androgen receptors control male sexual behavior and fertility, while the androgen-binding protein binds testosterone and maintains its concentration at optimal levels to stimulate spermatogenesis in the testis. It was found that piperine docks to the androgen-binding protein, similar to dihydrotestosterone, and to androgen receptors, similar to cyproterone acetate (antagonist). Also, the piperine-androgen-binding protein and piperine-androgen receptors interactions were found to be stable throughout 30 ns of molecular dynamics simulation. Further, two independent simulations for 10 ns each also confirmed the stability of these interactions. Detailed analysis of the piperine-androgen-binding protein interactions shows that piperine interacts with Ser42 of the androgen-binding protein and could block the binding with its natural ligands dihydrotestosterone/testosterone. Moreover, piperine interacts with Thr577 of the androgen receptors in a manner similar to the antagonist cyproterone acetate. Based on the in silico results, piperine was tested in the MDA-kb2 cell line using the luciferase reporter gene assay and was found to antagonize the effect of dihydrotestosterone at nanomolar concentrations. Further detailed biochemical experiments could help to develop piperine as an effective male contraceptive agent in the future.
[Mh] Termos MeSH primário: Alcaloides/química
Alcaloides/farmacologia
Proteína de Ligação a Androgênios/metabolismo
Benzodioxóis/química
Benzodioxóis/farmacologia
Anticoncepcionais Masculinos/farmacologia
Piperidinas/química
Piperidinas/farmacologia
Alcamidas Poli-Insaturadas/química
Alcamidas Poli-Insaturadas/farmacologia
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Alcaloides/metabolismo
Proteína de Ligação a Androgênios/química
Benzodioxóis/metabolismo
Domínio Catalítico
Linhagem Celular/efeitos dos fármacos
Simulação por Computador
Anticoncepcionais Masculinos/química
Di-Hidrotestosterona/farmacologia
Seres Humanos
Ligações de Hidrogênio
Masculino
Metribolona/química
Metribolona/metabolismo
Metribolona/farmacologia
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Piperidinas/metabolismo
Alcamidas Poli-Insaturadas/metabolismo
Conformação Proteica
Receptores Androgênicos/química
Serina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AR protein, human); 0 (Alkaloids); 0 (Androgen-Binding Protein); 0 (Benzodioxoles); 0 (Contraceptive Agents, Male); 0 (Piperidines); 0 (Polyunsaturated Alkamides); 0 (Receptors, Androgen); 08J2K08A3Y (Dihydrotestosterone); 2C323EGI97 (Metribolone); 452VLY9402 (Serine); U71XL721QK (piperine)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150710
[Lr] Data última revisão:
150710
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150604
[St] Status:MEDLINE
[do] DOI:10.1055/s-0035-1546082


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[PMID]:26033581
[Au] Autor:Didebulidze NA; Kakabadze MSh; Gordadze NG; Latsabidze IN; Kordzaya ME; Sikharulidze IT
[Ad] Endereço:I. A. Natishvili Institute of Experimental Morphology of I. Javakhishvili Tbilisi State University, Tbilisi, Georgia.
[Ti] Título:Correction of Hormonal and Metabolic Disorders in Male Rats with Developing Experimental Diabetes.
[So] Source:Bull Exp Biol Med;159(1):20-3, 2015 May.
[Is] ISSN:1573-8221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Synthetic radioinert androgen methyltrienolone administered daily for 2 weeks to male rats with severe diabetes led to a sharp increase in blood testosterone and was accompanied by reduction in glucose level due to an increase in tissue sensitivity to insulin. Normalization of plasma testosterone concentration contributed to saturation of active androgen receptors in the myocardium with testosterone; the number of free receptors decreased by 1.8 times. Testosterone that diminishes the catabolic effects of glucocorticoids improved the state of the myocardium, which was confirmed by activation of DNA and RNA synthesis.
[Mh] Termos MeSH primário: Anabolizantes/uso terapêutico
Diabetes Mellitus Experimental/tratamento farmacológico
Metribolona/uso terapêutico
Miocárdio/metabolismo
Testosterona/sangue
[Mh] Termos MeSH secundário: Anabolizantes/farmacocinética
Animais
Glicemia/análise
Corticosterona/sangue
Replicação do DNA
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Experimental/fisiopatologia
Estradiol/sangue
Hormônio do Crescimento/sangue
Coração/efeitos dos fármacos
Insulina/sangue
Resistência à Insulina
Masculino
Metribolona/farmacocinética
RNA/biossíntese
Ratos
Receptores Androgênicos/metabolismo
Testosterona/secreção
Distribuição Tecidual
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anabolic Agents); 0 (Blood Glucose); 0 (Insulin); 0 (Receptors, Androgen); 2C323EGI97 (Metribolone); 3XMK78S47O (Testosterone); 4TI98Z838E (Estradiol); 63231-63-0 (RNA); 9002-72-6 (Growth Hormone); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150609
[Lr] Data última revisão:
150609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150603
[St] Status:MEDLINE
[do] DOI:10.1007/s10517-015-2879-8


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[PMID]:25586052
[Au] Autor:Mitra R; Goodman OB
[Ad] Endereço:College of Biomedical Sciences, Roseman University of Health Sciences, Nevada.
[Ti] Título:CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR.
[So] Source:Prostate;75(5):527-38, 2015 Apr 01.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The central role of androgen receptor (AR) signaling is established in prostate cancer growth and progression. We propose CYP3A5 is part of a feedback loop that modulates the sensitivity of AR to androgen exposure. The purpose of this study is to elucidate the mechanism of regulation of AR expression by CYP3A5. METHODS: To identify the role of CYP3A5 in regulating AR signaling, CYP3A5 protein expression was inhibited using CYP3A5 siRNA and azamulin. Both cell fractionation and immunocytochemical approaches in combination with dihydrotestosterone (DHT) and R1881 treatment were used to evaluate changes in AR nuclear translocation. RESULTS: CYP3A5 siRNA blocked growth of LNCaP and C4-2 cells by 30-60% (P ≤ 0.005). Azamulin, a CYP3A pharmacologic inhibitor, reduced the growth of LNCaP, C4-2 and 22RV1 lines by ∼ 40% (P ≤ 0.005). CYP3A5 siRNA inhibited growth in response to DHT and R1881 treatment in LNCaP and C4-2 by decreasing nuclear AR localization and resulting in diminished PSA and TMPRSS2 expression. Decreased AR nuclear localization resulting from CYP3A5 inhibition resulted in growth inhibition comparable to IC60 and IC40 of bicalutamide in LNCaP and C4-2 cell lines. Conversely, the CYP3A inducer rifampicin enhanced AR nuclear localization. CONCLUSION: As CYP3A5 regulates the nuclear translocation of AR; co-targeting CYP3A5 may provide a novel strategy for enhancing the efficacy of androgen deprivation therapy. Consequentially, these data suggest that concomitant medications may impact androgen deprivation therapy's efficacy.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/fisiologia
Neoplasias da Próstata/enzimologia
Receptores Androgênicos/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Western Blotting
Hidrocarbonetos Aromáticos com Pontes/farmacologia
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP3A/farmacologia
Di-Hidrotestosterona/farmacologia
Imunofluorescência
Seres Humanos
Masculino
Metribolona/farmacologia
Neoplasias da Próstata/patologia
RNA Interferente Pequeno/farmacologia
Reação em Cadeia da Polimerase em Tempo Real
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AR protein, human); 0 (Bridged-Ring Compounds); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (RNA, Small Interfering); 0 (Receptors, Androgen); 0 (Triazoles); 08J2K08A3Y (Dihydrotestosterone); 2C323EGI97 (Metribolone); 875AQ866X1 (azamulin); EC 1.14.14.1 (CYP3A5 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150115
[St] Status:MEDLINE
[do] DOI:10.1002/pros.22940


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[PMID]:25476896
[Au] Autor:Castoria G; Giovannelli P; Di Donato M; Ciociola A; Hayashi R; Bernal F; Appella E; Auricchio F; Migliaccio A
[Ad] Endereço:Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
[Ti] Título:Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells.
[So] Source:Cell Death Dis;5:e1548, 2014 Dec 04.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions.
[Mh] Termos MeSH primário: Di-Hidrotestosterona/farmacologia
Filaminas/metabolismo
Células Mesenquimais Estromais/metabolismo
Receptores Androgênicos/metabolismo
Transdução de Sinais
Proteínas rac1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Inibidor de Quinase Dependente de Ciclina p27/genética
Inibidor de Quinase Dependente de Ciclina p27/metabolismo
Fibroblastos/citologia
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Fibrossarcoma/genética
Fibrossarcoma/metabolismo
Fibrossarcoma/patologia
Filaminas/genética
Regulação da Expressão Gênica
Seres Humanos
Masculino
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/efeitos dos fármacos
Metribolona/farmacologia
Camundongos
Células NIH 3T3
Fosforilação
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Tirosina Quinases/genética
Proteínas Tirosina Quinases/metabolismo
Receptores Androgênicos/genética
Serina/metabolismo
Congêneres da Testosterona/farmacologia
Células Tumorais Cultivadas
Proteínas rac1 de Ligação ao GTP/genética
Proteínas ras/genética
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AR protein, human); 0 (CDKN1B protein, human); 0 (Filamins); 0 (RAC1 protein, human); 0 (Receptors, Androgen); 0 (Testosterone Congeners); 08J2K08A3Y (Dihydrotestosterone); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); 2C323EGI97 (Metribolone); 452VLY9402 (Serine); EC 2.7.1.- (Dyrk kinase); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.6.5.2 (rac1 GTP-Binding Protein); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141206
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2014.497


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[PMID]:25294820
[Au] Autor:Nambiar DK; Deep G; Singh RP; Agarwal C; Agarwal R
[Ad] Endereço:Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. School of Life Sciences, Jawaharlal Nehru University, India.
[Ti] Título:Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1.
[So] Source:Oncotarget;5(20):10017-33, 2014 Oct 30.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.
[Mh] Termos MeSH primário: Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/metabolismo
Silimarina/farmacologia
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
[Mh] Termos MeSH secundário: Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Metabolismo dos Lipídeos/efeitos dos fármacos
Masculino
Metribolona/antagonistas & inibidores
Metribolona/farmacologia
Terapia de Alvo Molecular
Fosforilação
Neoplasias da Próstata/patologia
Neoplasias de Próstata Resistentes à Castração/prevenção & controle
Piridinas/farmacologia
Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores
Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese
Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores
Proteína de Ligação a Elemento Regulador de Esterol 2/biossíntese
Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
Tiazóis/farmacologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyridines); 0 (SREBF1 protein, human); 0 (SREBF2 protein, human); 0 (Silymarin); 0 (Sterol Regulatory Element Binding Protein 1); 0 (Sterol Regulatory Element Binding Protein 2); 0 (Thiazoles); 0 (fatostatin); 2C323EGI97 (Metribolone); 4RKY41TBTF (silybin)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141009
[St] Status:MEDLINE


  9 / 707 MEDLINE  
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[PMID]:25268119
[Au] Autor:Banuelos CA; Lal A; Tien AH; Shah N; Yang YC; Mawji NR; Meimetis LG; Park J; Kunzhong J; Andersen RJ; Sadar MD
[Ad] Endereço:Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
[Ti] Título:Characterization of niphatenones that inhibit androgen receptor N-terminal domain.
[So] Source:PLoS One;9(9):e107991, 2014.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD). Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD). Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S)-niphatenone had significantly better activity against the AR NTD compared to (R)-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR) activity and covalently bound to GR activation function-1 (AF-1) region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/farmacologia
Antineoplásicos Hormonais/farmacologia
Éteres de Glicerila/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Concentração Inibidora 50
Masculino
Metribolona/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Estrutura Terciária de Proteína
Receptores Androgênicos/química
Receptores Androgênicos/fisiologia
Estereoisomerismo
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (Antineoplastic Agents, Hormonal); 0 (Glyceryl Ethers); 0 (Receptors, Androgen); 0 (niphatenone B); 2C323EGI97 (Metribolone)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141001
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0107991


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[PMID]:25216853
[Au] Autor:Roediger J; Hessenkemper W; Bartsch S; Manvelyan M; Huettner SS; Liehr T; Esmaeili M; Foller S; Petersen I; Grimm MO; Baniahmad A
[Ti] Título:Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway.
[So] Source:Mol Cancer;13:214, 2014 Sep 12.
[Is] ISSN:1476-4598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. The androgen receptor (AR) and AR-agonists (androgens) are required for the development and progression of the normal prostate as well as PCa. However, it is discussed that in addition to their tumor promoting activity, androgens may also exhibit tumor suppressive effects. A biphasic growth response to androgens a growth-promoting and -inhibition has been observed that suggests that administration of supraphysiological androgen levels mediates growth reduction in AR expressing PCa cells. METHODS: Detection of senescence markers, three dimensional interphase fluorescence in situ hybridization (3D-iFISH), qRT-PCR, Western blotting, detection of GFP fusions, prostatectomy, ex vivo culturing. RESULTS: Here, we describe that supraphysiological levels of androgens induce cell cycle arrest and markers of cellular senescence in human PCa cells, which may in part explain the growth inhibitory role of androgens. The expression of the senescence associated beta galactosidase is observed by treatment with the natural androgen DHT or the less metabolized synthetic androgen R1881. The induction of senescence marker was detected in human PCa cell lines as well as in human primary PCa tissue derived from prostatectomy treated ex vivo. Using interphase FISH (iFISH) suggests that the androgen-induced cellular senescence is associated with localizing the genomic E2F1 locus to senescence associated heterochromatic foci. Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence. Based on the rapid induction of androgen-mediated cellular senescence we identified the Src-PI3K-Akt-signaling pathway and autophagy being in part involved in androgen regulation. CONCLUSIONS: Taken together, our data suggest that AR-agonists at supraphysiological levels mediate induction of cellular senescence in human PCa cells, which may have a protective anti-cancer role. These results provide also new insights for understanding androgen-mediated regulation of PCa growth.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Biomarcadores Tumorais/genética
Di-Hidrotestosterona/farmacologia
Metribolona/farmacologia
Neoplasias da Próstata/patologia
[Mh] Termos MeSH secundário: Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Senescência Celular
Fator de Transcrição E2F1/genética
Seres Humanos
Imagem Tridimensional
Hibridização in Situ Fluorescente
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/cirurgia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (E2F1 Transcription Factor); 0 (E2F1 protein, human); 08J2K08A3Y (Dihydrotestosterone); 2C323EGI97 (Metribolone)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140914
[St] Status:MEDLINE
[do] DOI:10.1186/1476-4598-13-214



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