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1.
Anticancer Res ; 41(3): 1377-1386, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788729

RESUMEN

BACKGROUND/AIM: The purpose of this study was to examine the expression of estrogen receptor α (ERα) and ß (ERß), androgen receptor (AR), SIRT1, SIRT2 and SIRT3 in prostate cancer (PCa). MATERIALS AND METHODS: From October 2010 to January 2015, 70 patients who had undergone radical prostatectomy following a PCa diagnosis were enrolled in our study. Normal prostate tissue (NPT) and prostate cancer tissues (PCAT) were separated, and the expression of each receptor in each tissue was analyzed with immunochemical staining. Univariate and multivariate analyses were performed to identify factors affecting the development of PCa. RESULTS: ERß and AR were highly expressed in PCAT compared with NPT (p<0.05). SIRT2 was highly expressed in NPT and PCAT (p<0.05). Univariate and multivariate analyses showed that AR and SIRT2 affect PCa development. CONCLUSION: AR is a risk factor for PC, and SIRT2 is associated with a lower incidence of PCa.


Asunto(s)
Receptor alfa de Estrógeno/biosíntesis , Receptor beta de Estrógeno/biosíntesis , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Sirtuina 1/biosíntesis , Sirtuina 2/biosíntesis , Sirtuina 3/biosíntesis , Anciano , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía
2.
Sci Rep ; 10(1): 22046, 2020 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-33328560

RESUMEN

The role of the Androgen Receptor (AR) expression and its activity in the prognosis of hepatocellular carcinoma (HCC) remains inconclusive. The aim of this study is to analyze the role of the AR expression and its activity as prognostic biomarkers in HCC. Three-hundred and thirty-seven patients from The Cancer Genome Atlas (TCGA) (107 females; 59.42 years [SD = 13.0]) were included. To infer AR activity, the expression-profile of previously validated androgen responsive genes (ARGs) was included. AR activity was shown by the AR-Score-21 (21 ARGs) and AR-Score-13 (13 ARGs) that were computed based on the expression of the selected ARGs. Those ARGs whose expression was significantly different between histological grades were used for computing two new AR-Scores. HCC patients with higher AR expression showed a higher median overall survival (OS). AR-Score 21 and AR-Score-13 did not show any association with prognosis. Six of the 21 ARGs of the AR-Score-21 and 7 of the 13 ARGs of the AR-Score-13 showed a significant different expression profile among histological grades. Based on these differences, another two AR-Scores were computed (AR-Score-6 and AR-Score-7). They showed the relative increase of upregulated to downregulated ARGs in high-grade HCC. Higher AR activity inferred by these AR-Scores was associated with worse outcomes. The expression of AR is associated with a better prognosis in HCC. However, the activity of the AR seems to be qualitatively different among histological grades. The AR activity inferred by the shifted ARGs is associated with a worse prognosis in HCC patients.


Asunto(s)
Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Proteínas de Neoplasias/biosíntesis , Receptores Androgénicos/biosíntesis , Anciano , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Supervivencia
3.
Prostate ; 80(13): 1097-1107, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32628300

RESUMEN

BACKGROUND: Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. METHODS: To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. RESULTS: Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). CONCLUSIONS: Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.


Asunto(s)
Calicreínas/biosíntesis , Neoplasias de la Próstata/enzimología , Anciano , Humanos , Inmunohistoquímica , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Fenotipo , Pronóstico , Antígeno Prostático Específico/biosíntesis , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Regulador Transcripcional ERG/biosíntesis , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo
4.
Prostate ; 80(12): 950-961, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32648618

RESUMEN

BACKGROUND: Prostate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism. METHODS: CPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration-resistant prostate cancer (CRPC) cell lines 22RV1 and C4-2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit-8 (CCK-8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR-binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide-resistant C4-2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4-2 was explored through CCK-8 test. RESULTS: CPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease-free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S-phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G-protein-coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK-8 experiment demonstrated that CPT1B overexpression in C4-2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4-2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation. CONCLUSIONS: CPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug-resistant line C4-2R, overexpression of CPT1B can promote the resistance of C4-2R to enzalutamide.


Asunto(s)
Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Estudios de Casos y Controles , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Regulación hacia Abajo , Resistencia a Antineoplásicos , Humanos , Masculino , Terapia Molecular Dirigida , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal
5.
Prostate ; 80(12): 1012-1023, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32649013

RESUMEN

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Asunto(s)
Células Neuroendocrinas/patología , Tumores Neuroendocrinos/patología , Neoplasias de la Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Diferenciación Celular/fisiología , Estudios de Cohortes , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Células Neuroendocrinas/metabolismo , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Estudios Retrospectivos , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
6.
Prostate ; 80(13): 1058-1070, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32692871

RESUMEN

BACKGROUND: Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cells in vitro. However, the status of NFIB in prostate cancer was unknown. METHODS: We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlate NFIB expression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blot analysis and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed co-immunoprecipitation studies to determine if NFIB and AR interact. RESULTS: NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castration-resistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples, NFIB expression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through co-immunoprecipitation experiments. CONCLUSION: We have described the expression pattern of NFIB in primary and castration-resistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.


Asunto(s)
Factores de Transcripción NFI/biosíntesis , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Línea Celular Tumoral , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Factores de Transcripción NFI/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Análisis de Matrices Tisulares , Transcriptoma
7.
Prostate ; 80(12): 993-1005, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32559345

RESUMEN

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance. METHODS: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models. RESULTS: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice. CONCLUSIONS: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.


Asunto(s)
Piperidinas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata Resistentes a la Castración/patología , Distribución Aleatoria , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/metabolismo , Survivin/antagonistas & inhibidores , Survivin/biosíntesis , Ubiquitinación , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Prostate ; 80(10): 742-752, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32449811

RESUMEN

BACKGROUND: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells. METHODS: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism. RESULTS: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. CONCLUSIONS: We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.


Asunto(s)
Docetaxel/efectos adversos , Células Asesinas Naturales/efectos de los fármacos , Lectinas Tipo C/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Receptores Androgénicos/inmunología , Receptores de Superficie Celular/inmunología , Antagonistas de Receptores Androgénicos/farmacología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Técnicas de Cocultivo , Terapia Combinada , Curcumina/análogos & derivados , Curcumina/farmacología , Docetaxel/uso terapéutico , Células HEK293 , Humanos , Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/trasplante , Lectinas Tipo C/antagonistas & inhibidores , Lectinas Tipo C/biosíntesis , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/biosíntesis , Regulación hacia Arriba/efectos de los fármacos
10.
Inflamm Res ; 69(2): 167-178, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31865399

RESUMEN

OBJECTIVE: To elucidate the regulation, function of the chemokine CXC-motif ligand 12 (CXCL12) and its receptors (CXCR) 4 and 7 in prostate cancer tumor microenvironment. MATERIAL: In-silico-analysis of expression in prostate cancer tissues. In-vitro comparison, testing of regulation in human prostate cancer cells LNCaP, DU145, and PC3. TREATMENT: Dihydrotestosterone (DHT) treatments (0-10 nM) were for 0-48 h. The inflammatory agent Flagellin treatment (20 ng/ml) was for 2 h. Migration assays were performed for 24 h using 10 ng/ml CXCL12. METHODS: Real-time PCR, western analysis, and migration assays were used to determine mRNA, protein, and functional changes, respectively. RESULTS: Malignant prostate cancer tissues exhibit higher CXCR4/7 mRNA ratio, and higher CXCR7 mRNA levels were detected in the androgen-responsive LNCaP cells. Putative androgen-responsive elements were identified in CXCR4, 7 gene, and exposure to DHT, flagellin increased CXCR4 mRNA but decreased CXCR7 mRNA levels in LNCaP cells. Androgen receptor siRNA significantly attenuated the effects of DHT on CXCR4, 7 mRNA in LNCaP cells. However, DHT and flagellin only decrease CXCR7 protein and additively increased migration of LNCaP cells towards CXCL12. CONCLUSIONS: Down regulation of CXCR7 protein by DHT and flagellin increased migration, supporting CXCR7 as decoy receptor counteracting CXCL12/CXCR4-mediated migration in prostate cancer cells.


Asunto(s)
Andrógenos/metabolismo , Inflamación/metabolismo , Neoplasias de la Próstata/genética , Receptores CXCR4/genética , Receptores CXCR/genética , Línea Celular Tumoral , Movimiento Celular , Quimiocina CXCL12/biosíntesis , Quimiocina CXCL12/genética , Simulación por Computador , Dihidrotestosterona/farmacología , Flagelina/farmacología , Humanos , Masculino , Neoplasias de la Próstata/patología , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores CXCR/biosíntesis , Receptores CXCR4/biosíntesis , Microambiente Tumoral
11.
Prostate ; 80(2): 133-145, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31730277

RESUMEN

BACKGROUND: The androgen receptor (AR) nuclear transcription factor is a therapeutic target for prostate cancer (PCa). Unfortunately, patients can develop resistance to AR-targeted therapies and progress to lethal disease, underscoring the importance of understanding the molecular mechanisms that underlie treatment resistance. Inflammation is implicated in PCa initiation and progression and we have previously reported that the inflammatory cytokine, interleukin-1 (IL-1), represses AR messenger RNA (mRNA) levels and activity in AR-positive (AR+ ) PCa cell lines concomitant with the upregulation of prosurvival biomolecules. Thus, we contend that IL-1 can select for AR-independent, treatment-resistant PCa cells. METHODS: To begin to explore how IL-1 signaling leads to the repression of AR mRNA levels, we performed comprehensive pathway analysis on our RNA sequencing data from IL-1-treated LNCaP PCa cells. Our pathway analysis predicted nuclear factor kappa B (NF-κB) p65 subunit (RELA), a canonical IL-1 signal transducer, to be significantly active and potentially regulate many genes, including AR. We used small interfering RNA (siRNA) to silence the NF-κB family of transcription factor subunits, RELA, RELB, c-REL, NFKB1, or NFKB2, in IL-1-treated LNCaP, C4-2, and C4-2B PCa cell lines. C4-2 and C4-2B cell lines are castration-resistant LNCaP sublines and represent progression toward metastatic PCa disease, and we have previously shown that IL-1 represses AR mRNA levels in C4-2 and C4-2B cells. RESULTS: siRNA revealed that RELA alone is sufficient to mediate IL-1 repression of AR mRNA and AR activity. Intriguingly, while LNCaP cells are more sensitive to IL-1-mediated repression of AR than C4-2 and C4-2B cells, RELA siRNA led to a more striking derepression of AR mRNA levels and AR activity in C4-2 and C4-2B cells than in LNCaP cells. CONCLUSIONS: These data indicate that there are RELA-independent mechanisms that regulate IL-1-mediated AR repression in LNCaP cells and suggest that the switch to RELA-dependent IL-1 repression of AR in C4-2 and C4-2B cells reflects changes in epigenetic and transcriptional programs that evolve during PCa disease progression.


Asunto(s)
Interleucina-1/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Factor de Transcripción ReIA/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-1alfa/farmacología , Masculino , FN-kappa B/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Androgénicos/genética , Factor de Transcripción ReIA/genética
12.
Arch Pathol Lab Med ; 144(3): 320-325, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31644322

RESUMEN

CONTEXT.­: The incidence of neuroendocrine tumors of the prostate increases after hormonal therapy. Neuroendocrine tumors possess a broad spectrum of morphologic features and pose challenges in the pathologic diagnosis and clinical management of patients. OBJECTIVE.­: To present a brief updated summary of neuroendocrine tumors of the prostate with an overview of their histopathologic and immunohistochemical profiles and differential diagnoses. DATA SOURCES.­: Literature review, personal experience in the daily practice of pathologic diagnosis, and laboratory research. CONCLUSIONS.­: Our understanding of neuroendocrine tumors of the prostate classification and diagnosis continues to evolve. These advances benefit the risk stratification and management of prostate cancer.


Asunto(s)
Adenocarcinoma/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Cromogranina A/biosíntesis , Diagnóstico Diferencial , Humanos , Inmunohistoquímica/métodos , Masculino , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/terapia , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Receptores Androgénicos/biosíntesis , Sinaptofisina/biosíntesis
13.
Mol Oncol ; 13(12): 2616-2632, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31520575

RESUMEN

The androgen receptor (AR) plays key roles in the development of prostate tissue and the development and progression of prostate cancer (PC). AR guides cytodifferentiation and homeostasis in benign luminal epithelial cells; however, in PC, AR instead drives the uncontrolled proliferation of these cells. This 'AR malignancy shift' (AMS) is a central event in tumorigenesis. Using a ChIP-seq approach in primary human tissues, cell lines, and mouse models, we demonstrate that the AMS occurs in every sample analyzed, suggesting that it is necessary for PC development. Using molecular and genetic techniques, we demonstrate that forkhead box (FOX)A1, HOXB13, GATA2, and c-JUN are involved in the regulation of the AMS. AR-binding sites (ARBS) are enriched for FOX, HOX, and GATA motifs in PC cells but not for c-JUN motifs in benign cells. We show that the SPOP mutation commonly found in localized PCs can cause the AMS but is not transformative on its own and must be coupled to another mutation to transform cells. We show that the AMS occurs in mouse models of PC as well and that chronic low T, which is associated with increased PC risk and aggressiveness in humans, also causes the AMS in mice. We have discovered a previously unrecognized, fundamental tenet of PC, one which explains how and why AR signaling is different in cancer and benign cells. Our work has the potential to be used to stratify patients with localized PC for specific treatments. Furthermore, our work suggests that the AMS is a novel target for the treatment and/or prevention of PC.


Asunto(s)
Mutación , Proteínas de Neoplasias , Neoplasias de la Próstata , Receptores Androgénicos , Elementos de Respuesta , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
14.
Prostate ; 79(16): 1811-1822, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31503366

RESUMEN

BACKGROUND: Prostate cancer (PRCA) is an androgen-driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR-targeted therapies, there has been a rising interest in the expression of full-length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes. METHODS: Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full-length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning-based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments. RESULTS: Full-length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double-positive (AR+ /ARv7+ ) population in metastases compared to benign, and an increase of the double-negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double-positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double-negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years. CONCLUSIONS: Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.


Asunto(s)
Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Isoformas de Proteínas , Receptores Androgénicos/genética , Análisis de Matrices Tisulares
15.
Cancer Res ; 79(20): 5204-5217, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31431456

RESUMEN

Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer. SIGNIFICANCE: RNA splicing factor SF3B2 is essential for the generation of an androgen receptor (AR) variant that renders prostate cancer cells resistant to AR-targeting therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5204/F1.large.jpg.


Asunto(s)
Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de Neoplasias/fisiología , Neoplasias de la Próstata/genética , Factores de Empalme de ARN/fisiología , Empalme del ARN/fisiología , ARN Mensajero/metabolismo , ARN Neoplásico/metabolismo , Receptores Androgénicos/genética , Adenocarcinoma/patología , Secuencias de Aminoácidos , Animales , Simulación por Computador , Progresión de la Enfermedad , Compuestos Epoxi/farmacología , Exones/genética , Humanos , Macrólidos/farmacología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Orquiectomía , Fenotipo , Neoplasias de la Próstata/patología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Empalme del ARN/efectos de los fármacos , Empalme del ARN/genética , Factores de Empalme de ARN/antagonistas & inhibidores , Factores de Empalme de ARN/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Receptores Androgénicos/biosíntesis , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Psychiatry Res ; 280: 112503, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31446215

RESUMEN

Anxiety and depressive disorders are more prevalent in hypogonadal men. Low testosterone levels are associated with greater negative symptoms and impaired cognition in men with schizophrenia. Thus, androgens may contribute to brain pathophysiology in psychiatric disorders. We investigated androgen-related mRNAs in post-mortem dorsolateral prefrontal cortex of psychiatric disorders. We also assessed androgen receptor (AR) CAG trinucleotide repeat length, a functional AR gene variant associated with AR gene expression, receptor activity, and circulating testosterone. AR CAG repeat length was determined from genomic DNA and AR and 5α-reductase mRNAs measured using quantitative PCR in schizophrenia, bipolar disorder and control cases [n = 35/group; Stanley Medical Research Institute (SMRI) Array collection]. Layer-specific AR gene expression was determined using in situ hybridisation in schizophrenia, bipolar disorder, major depressive disorder and control cases (n = 15/group; SMRI Neuropathology Consortium). AR mRNA was increased in bipolar disorder, but was unchanged in schizophrenia, relative to controls. AR and 5α-reductase mRNAs were significantly positively correlated in bipolar disorder. AR CAG repeat length was significantly shorter in bipolar disorder relative to schizophrenia. AR mRNA expression was highest in cortical layers IV and V, but no layer-specific diagnostic differences were detected. Together, our results suggest enhanced cortical androgen action in people with bipolar disorder.


Asunto(s)
Trastorno Bipolar/metabolismo , Trastorno Depresivo Mayor/metabolismo , Corteza Prefrontal/metabolismo , Receptores Androgénicos/biosíntesis , Esquizofrenia/metabolismo , Adulto , Anciano , Andrógenos/biosíntesis , Andrógenos/genética , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Estudios de Casos y Controles , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Androgénicos/genética , Esquizofrenia/genética , Psicología del Esquizofrénico , Testosterona/metabolismo
17.
Malays J Pathol ; 41(2): 125-132, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31427547

RESUMEN

INTRODUCTION: Androgen receptor (AR) is the most frequently expressed biomarker in all subtypes of breast carcinoma. Triple negative breast carcinoma (TNBC) is breast carcinoma that lacks oestrogen and progesterone receptors immunoexpression as well as absence of HER2/neu gene amplification. This makes targeted therapy not feasible in this cancer and hence has poorer prognosis. Detecting AR expression could be another milestone in the management of TNBC, as AR is a prognostic, predictive marker and potential index for targeted treatment. This study aimed to assess expression of AR in TNBC by immunohistochemistry and its association with clinicopathological parameters. METHODS: We analysed the expression of AR in 97 TNBC cases from Penang General Hospital for a period of 3 years (2014 to 2017). Androgen receptor immunoreactivity was considered positive if ≥ 1% of tumour cells nuclei were stained irrespective of staining intensity. RESULTS: The prevalence of AR expression in TNBC was 31% (30/97), with the proportion of AR-positive tumour cells ranged from 1% to 90%. These include 23 invasive carcinomas, no special type (NST) and 7 other invasive carcinoma subtypes (papillary, lobular, clear cell and medullary carcinomas). Sixty-seven cases (69%) that showed AR immunonegativity were invasive carcinomas, NST (n=60), clear cell carcinoma (n=1) and metaplastic carcinoma (n=6). Androgen receptor immunoexpression was inversely correlated with tumour grade (p=0.016), but not the tumour stage, tumour size and nodal status. CONCLUSION: AR is expressed in about one-third of TNBC and loss of AR immunoexpression does not predict adverse clinical outcomes. Larger cohorts for better characterisation of the role of AR immunoexpression in TNBC are warranted.


Asunto(s)
Carcinoma/patología , Receptores Androgénicos/biosíntesis , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad
18.
Cells ; 8(7)2019 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-31295943

RESUMEN

Aberrant activation of signaling pathways is frequently observed and reported to be associated with the progression and poor prognosis of prostate cancer (PCa). We aimed to identify key biological processes regulated by androgen receptor (AR) using gene co-expression network from single cell resolution. The bimodal index was used to evaluate whether two subpopulations exist among the single cells. Gene expression among single cells revealed averaging pitfalls and bimodality pattern. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of highly correlated genes. Twenty-nine gene modules were identified and AR-regulated modules were screened by significantly overlapping reported androgen induced differentially expressed genes. The biological function "generation of precursor metabolites and energy" was significantly enriched by AR-regulated modules with bimodality, presenting differential androgen response among subpopulations. Integrating with public ChIP-seq data, two genes FECH, and CROT has AR binding sites. Public in vitro studies also show that androgen regulates FECH and CROT. After receiving androgen deprivation therapy, patients lowly express FECH and CROT. Further survival analysis indicates that FECH/CROT signature can predict PCa recurrence. We reveal the heterogeneous function of "generation of precursor metabolites and energy" upon androgen stimulation from the perspective of single cells. Inhibitors targeting this biological process will facilitate to prevent prostate cancer progression.


Asunto(s)
Carnitina Aciltransferasas/genética , Ferroquelatasa/genética , Neoplasias de la Próstata/genética , Antagonistas de Andrógenos , Andrógenos , Carnitina Aciltransferasas/metabolismo , Línea Celular Tumoral , Bases de Datos Genéticas , Ferroquelatasa/metabolismo , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Humanos , Masculino , Recurrencia Local de Neoplasia/genética , Pronóstico , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal/genética , Análisis de la Célula Individual/métodos , Transcriptoma/genética
19.
Am J Physiol Endocrinol Metab ; 317(5): E731-E741, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31287713

RESUMEN

We previously demonstrated that androgen signaling expands pancreatic ß-cell mass in the sexual maturation period (Am J Physiol Endocrinol Metab 314: E274-E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in ß-cell mass development and ß-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive ß-cell precursor cells but was markedly reduced in insulin-positive ß-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced ß-cell mass and Ki67-positive proliferating ß-cells at birth in a male-specific manner without affecting body weight. The decrease of ß-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to ß-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic ß-cell function.


Asunto(s)
Andrógenos/metabolismo , Dieta Alta en Grasa , Enfermedades del Sistema Endocrino/patología , Feto/fisiopatología , Intolerancia a la Glucosa/metabolismo , Células Secretoras de Insulina/patología , Antagonistas de Andrógenos/farmacología , Animales , Composición Corporal , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Enfermedades del Sistema Endocrino/metabolismo , Enfermedades del Sistema Endocrino/fisiopatología , Femenino , Flutamida/farmacología , Intolerancia a la Glucosa/etiología , Secreción de Insulina/efectos de los fármacos , Metabolismo de los Lípidos , Masculino , Embarazo , Ratas , Ratas Wistar , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Caracteres Sexuales , Transducción de Señal
20.
Prostate ; 79(13): 1543-1552, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31299104

RESUMEN

BACKGROUND: Currently, antiprostate cancer (PCa) drugs, including androgen deprivation therapy (ADT), are initially effective; however, most patients with PCa who receive ADT eventually progress to deadly aggressiveness. There is an urgent need to seek alternative strategies to cure this lethal disease. Activation of lipogenesis has been demonstrated to lead to PCa progression. Therefore, targeting the aberrant lipogenic activity could be developed therapeutically in PCa. The aim of this study is to investigate the molecular basis and efficacy of osajin, a bioactive prenylated isoflavonoid, in PCa. METHODS: PCa cells, LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant), were used in this study. Proliferation, migration, and invasion analyses were conducted by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, a wound healing assay, and the transwell method. Lipogenesis was determined by a Fatty Acid Quantification Kit and oil red O staining. Apoptosis was assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, caspase enzymatic activity, and Western blot analyses. RESULTS: Osajin inhibited fatty acid synthase (FASN) expression, a key enzyme for lipogenesis, in PCa cells. By inhibiting FASN, osajin decreased the fatty-acid levels and lipid accumulation. Significantly, osajin downregulated androgen receptor (AR) and prostate-specific antigen (PSA) in PCa cells. Moreover, osajin suppressed PCa cell growth, migration, and invasion. Through activation of the caspase-dependent pathway, osajin induced apoptosis in PCa cells. CONCLUSIONS: These data provide a novel molecular basis of osajin in PCa cells, and cotargeting lipogenesis and the AR axis via impairment of FASN and AR expression by osajin could be applied as a new and promising approach for the treatment of malignant PCa.


Asunto(s)
Acido Graso Sintasa Tipo I/antagonistas & inhibidores , Isoflavonas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/biosíntesis , Apoptosis/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Acido Graso Sintasa Tipo I/metabolismo , Humanos , Calicreínas/metabolismo , Lipogénesis/efectos de los fármacos , Masculino , Invasividad Neoplásica , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/patología
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