Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.599
Filtrar
1.
Anticancer Res ; 39(10): 5541-5549, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570448

RESUMO

BACKGROUND/AIM: The connection between prostate cancer and inflammation has been proposed many years ago, but very little is known about the metabolic adaptations of prostate cells in case of infection or inflammation. The aim of this study was to examine the effect of the stimulation of Toll-like receptor 3 (TLR3) on the metabolism of prostate cancer (PCa) cell lines and benign prostate cells. MATERIALS AND METHODS: Cytofluorimetry, qRT-PCR, western blot and Gas-chromatography/Mass-spectrometry were used. RESULTS: Reprogramming of glucose utilization involving hypoxia-inducible factor 1-alpha (HIF-1α) and the extracellular adenosine axis was observed. TLR3 stimulation synergized with adenosine receptor A2b on PCa cells, and induced a strong production of lactate, exacerbating the Warburg effect. Moreover, stimulation of benign prostate cells with poly I:C reduced lactate secretion, a characteristic typical of the neoplastic transformation. CONCLUSION: TLR3 stimulation promotes metabolic adaptations likely involved in the mechanisms of disease onset and progression.


Assuntos
Glucose/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptor 3 Toll-Like/metabolismo , Adenosina/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Células PC-3 , Poli I-C/metabolismo , Neoplasias da Próstata/patologia , Receptores Purinérgicos P1/metabolismo
2.
J Steroid Biochem Mol Biol ; 195: 105484, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31574299

RESUMO

Vitamin D deficiency has been associated with increased risk for aggressive prostate cancer (PCa). Prostate epithelium has a unique metabolism compared to other tissues. Normal prostate exhibits low levels of mitochondrial respiration and there is a metabolic switch to increased oxidative phosphorylation in PCa. 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D and is used clinically to determine vitamin D status. Activation of 25(OH)D to the transcriptionally active form, 1,25(OH)2D occurs via a reduction-oxidation (redox) reaction within the mitochondria that is catalyzed by the P450 enzyme, CYP27B1. We sought to determine if hydroxylation of 25(OH)D by CYP27B1 contributes to non-genomic activity of vitamin D by altering the redox-dependent state of the mitochondria in benign prostate epithelial cells. Exposure to 25(OH)D produced a transient pro-oxidant effect and change in mitochondrial membrane potential that was dependent on CYP27B1. Extended exposure ultimately suppressed mitochondrial respiration, consistent with a protective effect of 25(OH)D in supporting benign prostate metabolism. To model physiologically relevant changes in vitamin D, cells were cultured in constant 25(OH)D then changed to high or deficient concentrations. This model also incurred a biphasic effect with a pro-oxidant shift after short exposure followed by decreased respiration after 16 h. Several genes involved in redox cycling and Mitochondrial Health were regulated by 25(OH)D in these cells. These results indicate a secondary non-genomic mechanism for vitamin D to contribute to prostate cell health by supporting normal mitochondrial respiration.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Mitocôndrias/efeitos dos fármacos , Próstata/citologia , Próstata/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Genômica , Humanos , Hidroxilação/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , RNA Interferente Pequeno/genética , Receptores de Calcitriol/genética
3.
Medicine (Baltimore) ; 98(38): e17257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567999

RESUMO

Recent availability of immune checkpoint inhibitors has facilitated research involving programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1). However, the incidence and clinical implication of PD-1 and PD-L1 expression in prostate cancer remain poorly understood. The current study aimed to determine the status of PD-1/PD-L1 expression in prostate cancer specimens and its prognostic significance.We immunohistochemically stained for PD-1 and PD-L1 in our tissue microarray (TMA) consisting of radical prostatectomy specimens. The expression of PD-1/PD-L1 was designated as positive when moderate to strong staining or weak staining was seen in at least 1% or 10%, respectively, of tumor cells and/or associated immune cells. We then evaluated the relationship between the expression of each protein and clinicopathological features available for our patient cohort.PD-1 and PD-L1 were positive in 3 (1.5%) and 1 (0.5%) of 201 non-neoplastic prostate tissues, and also in 17 (7.7%) and 29 (13.2%) of 220 prostate cancers, respectively. PD-1 and PD-L1 were also expressed in tumor-infiltrating lymphocytes/macrophages in 172 (78.2%) and 33 (15.0%) cases, respectively. PD-L1 expression in tumor cells was more often seen in high pT stage (pT2: 10.8% vs pT3/4: 20.4%; P = .072; pT2/3a: 11.4% vs pT3b/4: 31.6%; P = .013) or lymph node-positive (pN0: 10.1% vs pN1: 27.3%; P = .086) cases, whereas PD-1 expression in tumor cells was not significantly associated with pT/pN stage. In addition, there were no statistically significant associations between PD-1/PD-L1 expression in tumor cells or tumor-infiltrating lymphocytes/macrophages versus patient age, preoperative prostate-specific antigen level, or Gleason score. Kaplan-Meier analysis coupled with log-rank test further revealed no significant associations between PD-1/PD-L1 expression in tumor cells (P = .619/P = .315), tumor-infiltrating lymphocytes/macrophages (P = .954/P = .155), or either or both of them (P = .964/P = .767) versus disease recurrence after radical prostatectomy.PD-1/PD-L1 expression was detected in a subset of prostate cancers. In particular, PD-L1 expression was considerably up-regulated in nonorgan-confined tumors. However, PD-1/PD-L1 expression in our TMA was found to be not very helpful in predicting tumor recurrence in prostate cancer patients who underwent radical prostatectomy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno B7-H1/imunologia , Biomarcadores , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Análise Serial de Tecidos
4.
Medicine (Baltimore) ; 98(33): e16848, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415412

RESUMO

BACKGROUND: The aim of this study was to investigate the expression of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) in expressed prostatic secretions (EPSs) of patients with chronic prostatitis (CP) and the expression of prostatic exosomal protein (PSEP) in urine, and to evaluate its correlation with the condition. METHODS: Urine samples from 310 patients with CP (101 National Institutes of Health [NIH] II, 112 NIH IIIa, and 97 NIH IIIb, classified according to the US National Institutes of Health) and 110 control group subjects were collected. The samples were tested for PSEP by enzyme-linked immunosorbent assay (ELISA). At the same time, EPSs in 60 patients from 310 patients with CP and 20 control group subjects were collected. The levels of IL-10 and TNF-α in the collected samples that EPS were determined by double antibody sandwich ELISA. SPSS 23.0 statistical software was used for statistical analysis of the measured data. RESULTS: The level of PSEP in patients with CP was significantly higher than that in the control group (P < .001). The levels of TNF-α and IL-10 in the EPS of patients with NIH II and NIH IIIa CP were higher than those of the patients with NIH IIIb and the control group (P < .001). There was a positive correlation between PSEP and IL-10 and TNF-α, while TNF-α and IL-10 were also positively correlated. CONCLUSION: PSEP, TNF-α, and IL-10 may serve as a basis for the classification diagnosis of CP. Their combination can provide more accurate diagnostic information for clinical CP typing.


Assuntos
Exossomos/metabolismo , Interleucina-10/urina , Próstata/metabolismo , Prostatite/urina , Fator de Necrose Tumoral alfa/urina , Adulto , Biomarcadores/urina , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Pessoa de Meia-Idade , Prostatite/diagnóstico , Curva ROC , Adulto Jovem
5.
Mol Carcinog ; 58(11): 2077-2090, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31411358

RESUMO

The plasma membrane (PM) is considered as a major druggable site. More than 50% of the existing drugs target PM proteins. In the wake of emerging data indicating a key role of estrogens in prostate cancer (PCa) pathogenesis, the study was undertaken to explore whether the estrogen binding sites exist on the PM and if such sites are functionally relevant in PCa. Estradiol (E2) binding to the PM was detected in androgen-dependent (LNCaP), androgen-independent (PC3, DU145) PCa cell lines, nontumorigenic (RWPE1) prostate epithelial cell line, and rat prostate cells. Conventional estrogen receptors (nuclear estrogen receptors), known for their nuclear localization, were detected in the PM enriched extracts. This was indirectly confirmed by reduced localization of ERs on the PM of cells, silenced for the expression of their cognate genes. Further, unlike cell-permeable E2, stimulation with cell-impermeable estradiol (E2-BSA) did not induce proliferation in LNCaP cells. However, stimulation with E2-BSA led to alterations in the phosphorylation status of several kinases including GSK3 and AKT, along with the hyperphosphorylation of cytoskeletal proteins such as ß-actin and cytokeratin 8 in LNCaP. This was accompanied by epithelial-to-mesenchymal (EMT) features such as increased migration and invasion; higher vimentin expression, and a concomitant decrease in the E-cadherin expression. These effects were not observed in RWPE1 cells. Interestingly, cell-permeable E2 failed to induce EMT in PCa cells. This in vitro study is the first to suggest that the PM-initiated estrogen signaling contributes to higher invasiveness in PCa cells. Plasma membrane ERs may act as novel targets for PCa therapeutics.


Assuntos
Androgênios/metabolismo , Membrana Celular/genética , Estrogênios/metabolismo , Neoplasias da Próstata/genética , Animais , Caderinas/genética , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Transição Epitelial-Mesenquimal/genética , Estradiol/farmacologia , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/genética , Humanos , Queratina-8/genética , Masculino , Camundongos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Ratos , Transdução de Sinais
6.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395805

RESUMO

Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5-p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Neoplasias da Próstata/patologia , Androgênios/análise , Androgênios/metabolismo , Animais , Apoptose , Carcinogênese/metabolismo , Carcinogênese/patologia , Quinase 5 Dependente de Ciclina/análise , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Receptores Androgênicos/análise , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT3/análise , Fator de Transcrição STAT3/metabolismo
7.
Cell Mol Life Sci ; 76(24): 4849-4859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407019

RESUMO

The farnesoid-X-receptorα (FXRα; NR1H4) is one of the main bile acid (BA) receptors. During the last decades, through the use of pharmalogical approaches and transgenic mouse models, it has been demonstrated that the nuclear receptor FXRα controls numerous physiological functions such as glucose or energy metabolisms. It is also involved in the etiology or the development of several pathologies. Here, we will review the unexpected roles of FXRα on the male reproductive tract. FXRα has been demonstrated to play functions in the regulation of testicular and prostate homeostasis. Even though additional studies are needed to confirm these findings in humans, the reviewed reports open new field of research to better define the effects of bile acid-FXRα signaling pathways on fertility disorders and cancers.


Assuntos
Genitália Masculina/crescimento & desenvolvimento , Próstata/crescimento & desenvolvimento , Receptores Citoplasmáticos e Nucleares/genética , Testículo/crescimento & desenvolvimento , Animais , Ácidos e Sais Biliares/metabolismo , Genitália Masculina/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Próstata/metabolismo , Transdução de Sinais/genética , Testículo/metabolismo , Fatores de Transcrição/genética
8.
Anal Chim Acta ; 1081: 93-102, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31446969

RESUMO

Metabolomics analysis of biofluids is a feasible tool for disease characterization and monitoring due to its minimally invasive nature. To reduce unwanted variation in biobanks and clinical studies, it is important to determine the effect of external factors on metabolic profiles of biofluids. In this study we examined the effect of sample collection and sample processing procedures on NMR measured serum lipoproteins and small-molecule metabolites in serum and urine, using a cohort of men diagnosed with either prostate cancer or benign prostatic hyperplasia. We determined day-to-day reliability of metabolites by systematic sample collection at two different days, in both fasting and non-fasting conditions. Study participants received prostate massage the first day to assess the differences between urine with and without prostate secretions. Further, metabolic differences between first-void and mid-stream urine samples, and the effect of centrifugation of urine samples before storage were assessed. Our results show that day-to-day reliability is highly variable between metabolites in both serum and urine, while lipoprotein subfractions possess high reliability. Further, fasting status clearly influenced the metabolite concentrations, demonstrating the importance of keeping this condition constant within a study cohort. Day-to-day reliabilities were however comparable in fasting and non-fasting samples. Urine sampling procedures such as sampling of first-void or mid-stream urine, and centrifugation or not before sample storage, were shown to only have minimal effect on the overall metabolic profile, and is thus unlikely to constitute a confounder in clinical studies utilizing NMR derived metabolomics.


Assuntos
Metabolômica/métodos , Próstata/metabolismo , Urina/química , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Manejo de Espécimes
9.
Endocrinology ; 160(11): 2692-2708, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433456

RESUMO

Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERß and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERß to the cell membrane with caveolin-1 interactions. Exposure to 17ß-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2-dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERß in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERß selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERß, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERß membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Próstata/metabolismo , Caveolina 1/metabolismo , Células Cultivadas , Histona Metiltransferases/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Fosfotransferases/metabolismo , Próstata/citologia
10.
Int J Hyperthermia ; 36(1): 915-925, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31466481

RESUMO

Purpose: Prostate cancer can be eradicated with heat exposure. However, high and rapid temperature elevations may cause thermofixation giving the appearance of viable tissue. The purpose was to characterize the immunoprofile and evaluate the viability of prostate regions with suspected thermofixation. Methods and materials: A prospective, ethics-approved and registered study (NCT03350529) enrolled six patients with MRI-visible, biopsy-concordant prostate cancer to undergo lesion-targeted MRI-guided transurethral ultrasound ablation (TULSA) followed by radical prostatectomy at 3 weeks, to evaluate the accuracy and efficacy of TULSA with whole-mount histology as a reference standard. If ambiguity about complete necrosis within the ablated region remained after hematoxylin-eosin staining, viability was assessed by immunohistochemistry. Treatment day MRI-thermometry and 3-week contrast-enhanced MRI post-TULSA were examined to assess ablation success and correlation with histopathology. Results: One patient presented with an apparently viable subregion inside the ablated area, surrounded by necrosis on H&E staining, located where temperature was highest on MRI-thermometry and tissues completely devascularized on MRI. Immunoprofile of the apparently viable tissue revealed changes in staining patterns suggesting thermofixation; the most significant evidence was the negative cytokeratin 8 staining detected with Cam5.2 antibody. A comprehensive literature review supports these observations of thermofixation with similar findings in prostate and other tissues. Conclusion: Thermally-fixed cells can sustain morphology on H&E staining. Misinterpretation of treatment failure may occur, if this phenomenon is not recognized and immunohistochemistry performed. Based on the previous literature and the current study, Cam5.2 staining for cytokeratin 8 appears to be a practical and reliable tool for distinguishing thermally-fixed from viable cells.


Assuntos
Técnicas de Ablação , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Terapia por Ultrassom , Morte Celular , Humanos , Queratina-8/metabolismo , Imagem por Ressonância Magnética , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
11.
Anticancer Res ; 39(8): 4171-4177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366502

RESUMO

BACKGROUND/AIM: Identification of prostatic stem cells in primary prostate tissue sections, organ cultures of prostate and cell lines requires a range of techniques that allows characterization of stem cells for their potential use in the treatment of patients. Isolated cells usually round-up and develop changes in shape, size and cellular characteristics. The aim of this study was to provide a range of methods for identifying prostatic stem cells and characterizing them with regard to ultrastructure, nuclear morphology, cytoplasmic organelles, and/or expression stem cell marker CD133. MATERIALS AND METHODS: Prostate biopsy and prostatectomy specimens were used for studying prostatic stem cells and their known marker CD133 in tissue sections by light and/or electron microscopy. Inverted capsule embedding was used to study archival metastatic prostate in pelvic nodes and Du145 cell line in a monolayer culture. RESULTS: Staining for CD133 positively identified stem cells that were found in benign prostatic hyperplasia, benign prostate, and prostate cancer cells. Paraffin embedded sections showed a single type of stem cells, whereas methylene blue-stained Epon sections showed both light and dark stem cells. Electron microscopy showed that both basal and stem cells were closely associated with the basement membrane (basal lamina). Stem cells had smooth plasma and nuclear membranes, a prominent nucleolus, small mitochondria, and few ribosomes. Du145 cells were separated by intercellular spaces in monolayer culture. CONCLUSION: The inverted capsule embedding method allowed the study of metastasized prostate cancer in pelvic lymph nodes. Our approach enabled the assessment of stem cells in tissue sections by light and electron microscopy.


Assuntos
Antígeno AC133/genética , Membrana Basal/ultraestrutura , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Membrana Basal/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Microscopia Eletrônica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/ultraestrutura , Próstata/metabolismo , Próstata/patologia , Próstata/ultraestrutura , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/ultraestrutura
13.
J Clin Pathol ; 72(10): 696-704, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31331953

RESUMO

AIMS: Zinc-alpha 2-glycoprotein (AZGP1) is a promising tissue biomarker to predict outcomes in men undergoing treatment for localised prostate cancer (PCa). We aimed to examine the association between AZGP1 expression and the endpoints: risk of biochemical failure (BF), initiating castration-based treatment, developing castration-resistant PCa (CRPC) and PCa-specific mortality following radical prostatectomy (RP). METHODS: The study included a prospective cohort of 302 patients who underwent RP for PCa from 2002 to 2005. AZGP1 expression was analysed using immunohistochemistry on tissue microarray RP specimens and was scored semiquantitively as low or high expression. Risk of all endpoints was analysed using stratified cumulative incidences and cause-specific Cox regression, and validated with receiver operating curves, calibration and discrimination in competing-risk analyses. A meta-analysis was performed including previous studies investigating AZGP1 expression and risk of BF following RP. RESULTS: Median time of follow-up was 14.0 years. The cumulative incidence of all endpoints was significantly higher in patients with low AZGP1 expression compared with patients with high AZGP1 expression (p<0.001). In a multivariate analysis, low AZGP1 expression increases the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). Validation showed a low risk of prediction error and a high model performance for all endpoints. In a meta-analysis, low AZGP1 was associated with BF (HR 1.7; 95% CI 1.2 to 2.5). CONCLUSIONS: Low AZGP1 expression is associated with the risk of aggressive time-dependent outcomes in men undergoing RP for localised PCa.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo , Neoplasias da Próstata/metabolismo , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Análise Multivariada , Estudos Prospectivos , Próstata/metabolismo , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/cirurgia , Análise Serial de Tecidos
14.
Nat Commun ; 10(1): 3107, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308362

RESUMO

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.


Assuntos
Próstata/metabolismo , Neoplasias da Próstata/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transcriptoma
15.
Prostate ; 79(12): 1362-1377, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31269242

RESUMO

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in males in China. Long noncoding RNAs (lncRNAs) reportedly play crucial roles in human cancer progression in many studies. However, the molecular mechanisms underlying PCa progression remain unclear. MATERIALS AND METHODS: We investigated the lncRNA transcriptome using publicly available RNA-sequencing data to identify prostate-specific lncRNAs. Then, the chromatin immunoprecipitation (ChIP) assay identified lncRNA with a direct binding to androgen receptor (AR), hereafter denoted as PSLNR. Quantitative real-time polymerase chain reaction analysis and Western blot analysis were performed to detect the expression of p53 signaling-related genes after overexpression PSLNR. The effects of overexpression of PSLNR on cell proliferation, cell cycle, and cell apoptosis were assessed by using CCK-8 and flow cytometric analysis. We then detected the expression of PSLNR in tissues. RESULT: We reported a novel androgen-reduced prostate-specific lncRNA, PSLNR, that inhibited PCa progression via the p53-dependent pathway. By analyzing the NOCODE data set, we reported that PSLNR was specifically expressed in the prostate, suggesting the potential of PSLNR as a biomarker for PCa treatment. The AR pathway was also confirmed to be an upstream regulation signaling pathway of PSLNR by transcriptionally regulating its expression in androgen-dependent PCa cells. PSLNR also significantly inhibited PCa proliferation by inducing cell apoptosis in a p53-dependent manner. Thus, PSLNR may be a candidate diagnosis and therapeutic target for PCa. CONCLUSIONS: Our study revealed for the first time a novel androgen-reduced prostate-specific lncRNA, PSLNR, which inhibited PCa progression via the p53-dependent pathway, suggesting that PSLNR may be a candidate diagnosis and therapeutic target for PCa.


Assuntos
Biomarcadores Tumorais/genética , Genes p53/genética , Próstata/metabolismo , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Genes p53/fisiologia , Humanos , Masculino , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais
16.
Prostate ; 79(12): 1422-1438, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31269290

RESUMO

BACKGROUND: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. METHODS: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. RESULTS: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. CONCLUSIONS: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , MicroRNAs/biossíntese , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Receptor IGF Tipo 1/metabolismo , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Transdução de Sinais
17.
Inorg Chem ; 58(20): 13654-13660, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31260276

RESUMO

Prostatic zinc content is a known biomarker for discriminating normal healthy tissue from benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Given that zinc content is not readily measured without a tissue biopsy, we have been exploring noninvasive imaging methods to detect these diagnostic differences using a zinc-responsive MRI contrast agent. During imaging studies in mice, we observed that a bolus of glucose stimulates secretion of zinc from the prostate of fasted mice. This discovery allowed the use of a Gd-based zinc sensor to detect differential zinc secretion in regions of healthy versus malignant prostate tissue in a transgenic adenocarcinoma mouse model of PCa. Here, we used a zinc-responsive MRI agent to detect zinc release across the prostate during development of malignancy and confirm the loss of total tissue zinc by synchrotron radiation X-ray fluorescence (µSR-XRF). Quantitative µSR-XRF results show that the lateral lobe of the mouse prostate uniquely accumulates high concentrations of zinc, 1.06 ± 0.08 mM, and that the known loss of zinc content in the prostate is only observed in the lateral lobe during development of PCa. Additionally, we confirm that lesions identified by a loss of zinc secretion indeed represent malignant neoplasia and that the relative zinc concentration in the lesion is reduced to 0.370 ± 0.001 mM. The µSR-XRF data also provided insights into the mechanism of zinc secretion by showing that glucose promotes movement of zinc pools (∼1 mM) from the glandular lumen of the lateral lobe of the mouse prostate into the stromal/smooth muscle surrounding the glands. Co-localization of zinc and gadolinium in the stromal/smooth muscle areas as detected by µSR-XRF confirm that glucose initiates secretion of zinc from intracellular compartments into the extracellular spaces of the gland where it binds to the Gd-based agent and albumin promoting MR image enhancement.


Assuntos
Fluorescência , Glucose/química , Imagem por Ressonância Magnética , Próstata/química , Neoplasias da Próstata/química , Síncrotrons , Zinco/análise , Animais , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Próstata/citologia , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Raios X , Zinco/metabolismo
18.
BMC Bioinformatics ; 20(1): 385, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288758

RESUMO

BACKGROUND: In cancer research, robustness of a complex biochemical network is one of the most relevant properties to investigate for the development of novel targeted therapies. In cancer systems biology, biological networks are typically modeled through Ordinary Differential Equation (ODE) models. Hence, robustness analysis consists in quantifying how much the temporal behavior of a specific node is influenced by the perturbation of model parameters. The Conditional Robustness Algorithm (CRA) is a valuable methodology to perform robustness analysis on a selected output variable, representative of the proliferation activity of cancer disease. RESULTS: Here we introduce our new freely downloadable software, the CRA Toolbox. The CRA Toolbox is an Object-Oriented MATLAB package which implements the features of CRA for ODE models. It offers the users the ability to import a mathematical model in Systems Biology Markup Language (SBML), to perturb the model parameter space and to choose the reference node for the robustness analysis. The CRA Toolbox allows the users to visualize and save all the generated results through a user-friendly Graphical User Interface (GUI). The CRA Toolbox has a modular and flexible architecture since it is designed according to some engineering design patterns. This tool has been successfully applied in three nonlinear ODE models: the Prostate-specific Pten-/- mouse model, the Pulse Generator Network and the EGFR-IGF1R pathway. CONCLUSIONS: The CRA Toolbox for MATLAB is an open-source tool implementing the CRA to perform conditional robustness analysis. With its unique set of functions, the CRA Toolbox is a remarkable software for the topological study of biological networks. The source and example code and the corresponding documentation are freely available at the web site: http://gitlab.ict4life.com/SysBiOThe/CRA-Matlab .


Assuntos
Algoritmos , Modelos Biológicos , Neoplasias/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Simulação por Computador , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Humanos , Cinética , Masculino , Camundongos , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Próstata/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
19.
Urologiia ; (2): 73-81, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31162906

RESUMO

Prostate cancer (PCa) is the 4th most commonly diagnosed cancer in the male population and incidence of different stages is increasing every year. The efficiency of PCa treatment is strongly dependent on the its stage. Prostate Specific Antigen (PSA) is the most widely used and universal biomarker of PCa worldwide. Considering its limited predictive value, particularly in patients older than 50 with PSA level ranging from 4.5 to 10 ng/ml, there is a need to introduce new serum biomarkers of PCa. Current data on different PCa biomarkers are reviewed in the article as well as a role of angiotensin-converting enzyme (ACE) as a novel PCa biomarker.


Assuntos
Biomarcadores Tumorais/sangue , Peptidil Dipeptidase A/sangue , Hiperplasia Prostática/sangue , Neoplasias da Próstata/sangue , Humanos , Masculino , Próstata/metabolismo , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/diagnóstico
20.
Neoplasia ; 21(7): 713-720, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31151054

RESUMO

Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymerase II, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters cancer cell metabolism.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Quinase 9 Dependente de Ciclina/genética , Neoplasias da Próstata/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase 9 Dependente de Ciclina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Masculino , Oxirredução , Fosforilação Oxidativa , Fosforilação , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA