RESUMO
Benign prostatic hyperplasia (BPH) is the most common and progressive urological disease in elderly men worldwide. Epidemiological studies have suggested that the speed of disease progression varies among individuals, while the pathophysiological mechanisms of accelerated clinical progression in some BPH patients remain to be elucidated. In this study, we defined patients with BPH as belonging to the accelerated progressive group (transurethral resection of the prostate [TURP] surgery at ≤50 years old), normal-speed progressive group (TURP surgery at ≥70 years old), or non-progressive group (age ≤50 years old without BPH-related surgery). We enrolled prostate specimens from the three groups of patients and compared these tissues to determine the histopathological characteristics and molecular mechanisms underlying BPH patients with accelerated progression. We found that the main histopathological characteristics of accelerated progressive BPH tissues were increased stromal components and prostatic fibrosis, which were accompanied by higher myofibroblast accumulation and collagen deposition. Mechanism dissection demonstrated that these accelerated progressive BPH tissues have higher expression of the CYP19 and G protein-coupled estrogen receptor (GPER) with higher estrogen biosynthesis. Estrogen functions via GPER/Gαi signaling to modulate the EGFR/ERK and HIF-1α/TGF-ß1 signaling to increase prostatic stromal cell proliferation and prostatic stromal fibrosis. The increased stromal components and prostatic fibrosis may accelerate the clinical progression of BPH. Targeting this newly identified CYP19/estrogen/GPER/Gαi signaling axis may facilitate the development of novel personalized therapeutics to better suppress the progression of BPH.
Assuntos
Hiperplasia Prostática , Ressecção Transuretral da Próstata , Idoso , Aromatase/metabolismo , Estrogênios/metabolismo , Fibrose , Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/metabolismo , Hiperplasia Prostática/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Data analysis of clinical samples suggests that higher estrogen receptor α (ERα) expression could be associated with worse overall survival in some patients with non-small-cell lung cancer (NSCLC). Immunofluorescence results further showed that higher ERα expression was linked to larger numbers of infiltrated macrophages in NSCLC tissues. However, the detailed mechanisms underlying this phenomenon remain unclear. Results from in vitro studies with multiple cell lines revealed that, in NSCLC cells, ERα can activate the CCL2/CCR2 axis to promote macrophage infiltration, M2 polarization, and MMP9 production, which can then increase NSCLC cell invasion. Mechanistic studies using chromatin immunoprecipitation and promoter luciferase assays demonstrated that ERα could bind to estrogen response elements (EREs) on the CCL2 promoter to increase CCL2 expression. Furthermore, ERα-increased macrophage infiltration can induce a positive feedback mechanism to increase lung cancer cell ERα expression via the up-regulation of the CXCL12/CXCR4 pathway. Targeting these newly identified pathways, NSCLC ERα-increased macrophage infiltration or the macrophage-to-NSCLC CXCL12/CXCR4/ERα signal, with anti-estrogens or CCR2/CXCR4 antagonists, may help in the development of new alternative therapies to better treat NSCLC.
Assuntos
Quimiocina CCL2/metabolismo , Quimiocina CXCL12/metabolismo , Receptor alfa de Estrogênio/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Receptores CCR2/metabolismo , Receptores CXCR4/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Polaridade Celular , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Camundongos Nus , Modelos Biológicos , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The current chemotherapy regimens may extend survival for patients with metastatic bladder cancer (BCa) for a few months, but eventually most patients succumb to disease because they develop resistance to their chemotherapy. METHODS: TCGA human clinical sample survey and urothelial tumor tissue microarrays (TMAs) were applied to investigate the expression of androgen receptor (AR) and NF-κB. Multiple BCa cell lines were used to test chemotherapy's efficacy via multiple assays including XTT, flow cytometry, TUNEL, and BrdU incorporation. The effects of the AR degradation enhancer, ASC-J9®, combined with various chemotherapy reagents were examined both in vivo and in vitro. RESULTS: We unexpectedly found that in muscle-invasive BCa (miBCa) the signals of both the AR and NF-κB were increased via a TCGA sample survey. Results from multiple approaches revealed that targeting these two increased signals by combining various chemotherapeutic agents, including Cisplatin, Doxorubicin or Mitomycin C, with ASC-J9® led to increase the therapeutic efficacy. The combined therapy increases the expression of the pro-apoptosis BAX gene and cell cycle inhibitor p21 gene, yet suppresses the expression of the pro-survival BCL2 gene in miBCa cells. Preclinical studies using an in vivo mouse model with xenografted miBCa cells confirmed in vitro cell line data showing that treatment with ASC-J9® combined with Cisplatin can result in suppressing miBCa progression better than Cisplatin alone. CONCLUSIONS: Together, these results support a novel therapeutic approach via combining Cisplatin with ASC-J9® to better suppress the progression of miBCa.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Curcumina/análogos & derivados , NF-kappa B/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/uso terapêutico , Curcumina/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: While androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT. METHODS: We used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA. FINDINGS: We demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9®, but not the antiandrogen, Enzalutamide, could increase radiosensitivity via inducing DNA damage, altering the AR mediated and DNA repair pathways, and activating apoptosis. ASC-J9® had little effects on normal bladder cells. INTERPRETATION: Targeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9®, could increase the radiosensitivity while sparing adjacent normal tissue. Mechanism dissection revealed that ASC-J9®, but not Enzalutamide, treatment could increase radiosensitivity via inducing DNA damage, altering DNA repair pathways, as well as activating the IR-induced apoptosis via suppressing the pATR-CHK1 signals. Importantly, results from preclinical studies using an in vivo mouse model also demonstrated that combining RT with ASC-J9® to target AR led to better therapeutic efficacy to suppress PCa progression.
Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Curcumina/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Neoplasias da Próstata/terapia , Proteólise , Radiação , Radioterapia , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects.
Assuntos
Quimiocina CCL2/metabolismo , Curcumina/análogos & derivados , Prostatite/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/prevenção & controle , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Masculino , Camundongos Endogâmicos NOD , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Prostatite/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5ß1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Vacina BCG/farmacologia , Curcumina/análogos & derivados , Flutamida/análogos & derivados , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/farmacologia , Animais , Vacina BCG/administração & dosagem , Vacina BCG/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/farmacologia , Progressão da Doença , Sinergismo Farmacológico , Feminino , Flutamida/administração & dosagem , Flutamida/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfa5beta1/genética , Interleucina-6/genética , Macrófagos/efeitos dos fármacos , Camundongos , Receptores Androgênicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismoRESUMO
The male sex has a higher risk to develop coronary artery diseases, including atherosclerosis. The androgen receptor (AR) is expressed in several atherosclerosis-associated cell types, including monocytes/macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), but its pathophysiological role in each cell type during the development of atherosclerotic lesions remains unclear. Using the Cre-loxP system, we selectively knocked out AR in these 3 cell types and the resultant AR knockout (ARKO) mice, monocyte/macrophage ARKO, EC-ARKO, and SMC-ARKO, were then crossed with the low-density lipoprotein receptor (LDLR) deficient (LDLR(-/-)) mice to develop monocyte/macrophage ARKO-LDLR(-/-), EC-ARKO-LDLR(-/-), and SMC-ARKO-LDLR(-/-) mice for the study of atherosclerosis. The results showed that the monocyte/macrophage ARKO-LDLR(-/-) mice had reduced atherosclerosis compared with the wild-type-LDLR(-/-) control mice. However, no significant difference was detected in EC-ARKO-LDLR(-/-) and SMC-ARKO-LDLR(-/-) mice compared with wild-type-LDLR(-/-) mice, suggesting that the AR in monocytes/macrophages, and not in ECs and SMCs, plays a major role to promote atherosclerosis. Molecular mechanism dissection suggested that AR in monocytes/macrophages upregulated the tumor necrosis factor-α, integrin ß2, and lectin-type oxidized LDL receptor 1 molecules that are involved in 3 major inflammation-related processes in atherosclerosis, including monocytes/macrophages migration and adhesion to human umbilical vein ECs, and subsequent foam cell formation. Targeting AR via the AR degradation enhancer, ASC-J9, in wild-type-LDLR(-/-) mice showed similar effects as seen in monocyte/macrophage ARKO-LDLR(-/-) mice with little influence on lipid profile. In conclusion, the AR in monocytes/macrophages plays key roles in atherosclerosis and targeting AR with ASC-J9 may represent a new potential therapeutic approach to battle atherosclerosis.
Assuntos
Aterosclerose/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores Androgênicos/deficiência , Animais , Aterosclerose/genética , Aterosclerose/prevenção & controle , Western Blotting , Antígenos CD18/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Células Cultivadas , Curcumina/análogos & derivados , Curcumina/farmacologia , Dieta Hiperlipídica , Células Espumosas/citologia , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Monócitos/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptores Androgênicos/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 µm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-ß1/Smad3/MMP9 pathway, but ASC-J9® and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9® to battle PCa metastasis at the castration-resistant stage.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios , Anilidas/farmacologia , Curcumina/análogos & derivados , Nitrilas/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Benzamidas , Linhagem Celular Tumoral , Curcumina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Feniltioidantoína/farmacologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Transplante HeterólogoRESUMO
The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
Assuntos
Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Decitabina , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Orquiectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)-mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.
Assuntos
Regulação da Expressão Gênica/fisiologia , Hipotálamo/metabolismo , Resistência à Insulina/fisiologia , NF-kappa B/metabolismo , Neurônios/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/biossíntese , Receptores Androgênicos/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina/genética , Leptina/sangue , Leptina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade Abdominal/genética , Obesidade Abdominal/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten(+/-) mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.
Assuntos
Castração , Curcumina/análogos & derivados , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quimioprevenção , Curcumina/efeitos adversos , Curcumina/uso terapêutico , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Nus , Coativadores de Receptor Nuclear/metabolismo , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Próstata/efeitos dos fármacos , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Proteólise/efeitos dos fármacos , Receptores Androgênicos/genética , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Development and progression of prostate cancer are intimately associated with androgen receptor (AR) signaling. The emergence of hormone-refractory prostate cancer and consequent failure of conventional androgen deprivation therapies make it necessary to bypass hormonal resistance by targeting the same signaling pathway at new intervention points. In our study, we showed that cryptotanshinone inhibited the growth of AR-positive prostate cancer cells, suggesting that cryptotanshinone affected AR function. Cryptotanshinone also profoundly inhibited the transcriptional activity of AR and suppressed the expression of several AR-target genes at the mRNA and the protein levels. At the molecular level, cryptotanshinone disrupted the interaction between AR and lysine-specific demethylase 1 (LSD1), and inhibited the complex of AR and LSD1 to the promoter of AR target genes without affecting the protein degradation and translocation of AR. Cryptotanshinone increased the mono-methyl and di-methylation of Histone H3 lysine 9 (H3K9), a repressive histone marker which is demethylated and activated by LSD1. These data suggest that cryptotanshinone functions via inhibition of LSD1, a protein that promotes AR-dependent transcriptional activity via derepression of H3K9. In summary, we describe a novel mechanism whereby cryptotanshinone down-regulates AR signaling via functional inhibition of LSD1-mediated demethylation of H3K9 and represses the transcriptional activity of AR. Our data suggest that cryptotanshinone can be developed as a potential therapeutic agent for prostate cancer.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Histona Desmetilases/fisiologia , Fenantrenos/farmacologia , Receptores Androgênicos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , DNA/metabolismo , Regulação para Baixo , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Transdução de Sinais/fisiologiaRESUMO
Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selectively inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/metabolismo , Fenantrenos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Dimerização , Medicamentos de Ervas Chinesas/farmacologia , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Orquiectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Salvia miltiorrhiza/química , Ativação Transcricional/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND & AIMS: Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes. METHODS: By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC. RESULTS: We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models. CONCLUSIONS: Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.