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2.
Acta Oncol ; 58(9): 1205-1211, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31109224

RESUMO

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzyme defect worldwide. There is a growing scientific evidence for a protective role of G6PD deficiency against carcinogenesis. In this retrospective analysis, we tested the hypothesis that G6PD deficiency may reduce the risk of developing cancer in a tissue-specific manner. Material and methods: The study was conducted using data from 11,708 subjects undergoing gastrointestinal endoscopic procedures between 2002 and 2018 and tested for G6PD status in a teaching hospital of Northern Sardinia, Italy. Results: A 40% reduction of risk for cancer of endodermal origin was observed among G6PD-deficient patients compared with subjects with normal enzyme activity (relative risk (RR) 0.61, 95% confidence interval (CI) 0.47-0.80) in both genders, confirmed by multivariable generalized linear regression after adjusting for age, sex, smoking habits, body mass index, diabetes and socio-economic status. The 'protective' effect of G6PD deficiency was larger for gastric cancer (RR 0.41, 95% CI 0.18-0.99), hepatocellular carcinoma (RR 0.48, 95% CI 0.26-0.92) and colorectal cancer (RR 0.72, 95% CI 0.53-0.98), while a non-significant risk was observed for breast, prostate, lung, hematopoietic and metastases (primary site unknown). Conclusions: Our results suggest a reduced susceptibility to develop cancers, mostly of endodermal origin (stomach, colon and liver), but not of ectodermal/mesodermal origin, in carriers of G6PD deficiency. The effects of G6PD deficiency on carcinogenesis need further studies to better understand how cancer cells originating from different germ layers use pentose phosphate pathway to proliferate.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase/sangue , Neoplasias/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/enzimologia , Neoplasias da Mama/enzimologia , Carcinoma Hepatocelular/enzimologia , Estudos de Casos e Controles , Neoplasias Colorretais/enzimologia , Intervalos de Confiança , Suscetibilidade a Doenças , Feminino , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Humanos , Modelos Lineares , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Neoplasias da Próstata/enzimologia , Estudos Retrospectivos , Neoplasias Gástricas/enzimologia
3.
PLoS One ; 14(5): e0217373, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125365

RESUMO

INTRODUCTION: Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions including its catalytic activity towards producing extra-testicular androgen. The present study is towards understanding interaction between biological, lifestyle and genetic impacts of AKR1C3 and their influence on clinical factors in a prostate cancer (PC) cohort from New Zealand (NZ). METHOD: Characteristics of 516 PC patients were collected from the Auckland Regional Urology Facility, NZ. These men were genotyped for the AKR1C3 rs12529 single nucleotide polymorphism (SNP). The leukocyte AKR1C3 activity was measured in a sub-cohort. Variability of leukocyte AKR1C3 activity between biological, lifestyle and clinical features as well as correlation between biological and clinical features were assessed with and without genetic stratification. RESULTS: The leukocyte AKR1C3 activity was associated with age at diagnosis (0.51 vs 0.34 µM coumberol units for >69y vs ≤69y, P = 0.03); and with anatomic stage/prognostic grouping among the AKR1C3 rs12529 CC genotype carriers (0.50 vs 28 µM coumberol units among low- and high-risk groups respectively, P = 0.02). Significant correlation between leukocyte AKR1C3 activity and age at PC diagnosis was also observed (correlation coefficient 0.20 and P = 0.02). Ever- smoking impacted both age and PSA at PC diagnosis among AKR1C3 rs12529 GG and CG genotype carriers respectively. Age at diagnosis significantly correlated with PSA at diagnosis in the main (correlation coefficient 0.29, and P<0.001) and sub-cohorts (correlation coefficient 0.24, and P = 0.01); and those carrying the AKR1C3 rs12529 CG and GG genotypes in both the main (correlation coefficient 0.30, and P<0.001 and correlation coefficient 0.35, and P<0.001 respectively) and sub-cohorts (correlation coefficient 0.43, and P<0.001 and correlation coefficient 0.39, and P = 0.06 respectively); but not with those carrying the CC genotype. CONCLUSIONS: Age dependent PSA thresholds in PC screening could have been valid only in men carrying the AKR1C3 rs12529 CG and GG genotypes in this NZ cohort.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/sangue , Membro C3 da Família 1 de alfa-Ceto Redutase/genética , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Genótipo , Humanos , Calicreínas/sangue , Leucócitos/enzimologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Nova Zelândia , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia
4.
Cell Mol Biol (Noisy-le-grand) ; 65(3): 114-118, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30942164

RESUMO

Prostate cancer (PC) has become a disease that pose a serious threat to men's health and life. In recent years, due to the changes of environment, lifestyle and other factors, the incidence of PC has been increasing rapidly in recent years, which is a serious threat to men's health. Ent-Dihydrotucumanoic Acid (DTA) is a compound isolated from Asteraceae of gymnosperms, which has many pharmacological effects. The effect of DTA on the growth of tumor cell line was studied by CCK-8 method, mitochondrial membrane potential and apoptosis were detected by flow cytometry, apoptosis-related genes were detected by Western blot assay, and the absorptivity of Caspase-3 and Caspase-9 was measured by spectrophotometer. It was found that DTA induces apoptosis of human prostate cancer cell line PC3 through mitochondrial pathway, thus preventing the development of prostate cancer. It lays the experimental foundation for the further development of DTA.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Neoplasias da Próstata/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias da Próstata/enzimologia
5.
Prostate ; 79(9): 1053-1058, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30958903

RESUMO

Protein Kinase D1 (PrKD1) functions as a tumor and metastasis suppressor in several human cancers by influencing cell-cycle progression. However, the exact mechanism of cell-cycle regulation by PrKD1 is unclear. Overexpression and ectopic expression of PrKD1 induces G1 arrest in cancer cell lines. Because checkpoint kinases (CHEKs) are known to play a role in progression through the G1 phase, we downregulated CHEK1, which did not overcome the G1 arrest induced by PrKD1. Using in vitro phosphorylation and Western blot assays, we showed that PrKD1 phosphorylates all CDC25 isoforms (known substrates of CHEK kinases), independent from CHEK kinases, suggesting that direct phosphorylation of CDC25 by PrKD1 may be an alternate mechanism of G1 arrest. The study has identified a molecular mechanism for the influence of PrKD1 in cell-cycle progression.


Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Proteína Quinase C/metabolismo , Fosfatases cdc25/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Masculino , Fosforilação , Neoplasias da Próstata/metabolismo
6.
Med Sci Monit ; 25: 3090-3099, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026254

RESUMO

BACKGROUND In the pathogenesis and progression of prostate cancer, cell proliferation and cell migration results in tumor invasion and metastasis that is associated with patient morbidity and mortality. Rho-associated protein kinase (ROCK) has previously been shown to be upregulated in prostate cancer, but its biological role remains poorly understood. This study aimed to investigate the role of ROCK in the proliferation and migration of PC-3 and DU145 prostate cancer cells and to identify the possible targets involved by knockdown of ROCK1 and ROCK2 RNA expression. MATERIAL AND METHODS An RNA interference (RNAi) assay was performed to silence the expression of ROCK1 and ROCK2 in the PC-3 and DU145 human prostate cancer cell lines. Cells were also treated with a specific ROCK inhibitor, Y27632. A cell counting kit-8 (CCK-8) assay was used to determine the proliferation rate of prostate cancer cells, and cell migration and invasion assays were performed. Western blot and polymerase chain reaction were used to measure protein and RNA expression levels. RESULTS In PC-3 and DU145 prostate cancer cells, knockdown of ROCK1 and ROCK2 reduced cell migration and invasion. ROCK1 and ROCK2 regulated cell proliferation in PC-3 and DU145 prostate cancer cells. Protein levels of phosphorylated LIM kinase 1 (p-LIMK1) and matrix metalloproteinase-2 (MMP-2) were reduced in ROCK1 and ROCK2 siRNA transfected cells. CONCLUSIONS In PC-3 and DU145 human prostate cancer cells, ROCK promoted cell proliferation and migration by targeting LIMK1 and MMP-2.


Assuntos
Quinases Lim/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Neoplasias da Próstata/enzimologia , Quinases Associadas a rho/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais , Quinases Associadas a rho/genética
7.
Molecules ; 24(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974737

RESUMO

Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1⁻G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 µM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.


Assuntos
Carbocianinas , Corantes Fluorescentes , Isoniazida , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Proteínas de Neoplasias , Neoplasias da Próstata , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Isoniazida/química , Isoniazida/farmacologia , Masculino , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
8.
Biosci Trends ; 13(2): 160-167, 2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-30944266

RESUMO

Plant sterols (phytosterols) have been widely accepted as a natural anti-cancer agent in multiple malignant tumors. This study was designed to investigate the functions of daucosterol in prostate cancer progression and its possible molecular mechanisms. Our results showed that daucosterol inhibited cell proliferation and induced cell cycle arrest. Moreover, daucosterol treatment obviously promoted apoptosis and autophagy. An autophagy inhibitor, 3-methyladenine (3-MA) was proved to counteract daucosterol-triggered autophagy, growth inhibition, and apoptosis, indicating that daucosterol-induced apoptotic response was dependent on autophagy. Additionally, treatment with daucosterol resulted in increased phosphorylation of c-Jun N-terminal kinase (JNK). Furthermore, pre-treatment with a JNK-specific inhibitor SP600125 abated daucosterol-elicited autophagy and apoptotic cell death. Taken together, our findings demonstrated that daucosterol blocked prostate cancer growth at least partly through inducing autophagic-dependent apoptosis via activating JNK signaling, providing a promising candidate for the development of antitumor drugs in prostate cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Sitosteroides/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Masculino
9.
Prostate ; 79(8): 896-908, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900312

RESUMO

Numerous genetic alterations have been identified during prostate cancer progression. The influence of environmental factors, particularly the diet, on the acceleration of tumor progression is largely unknown. Expression levels and/or activity of Src kinase are highly elevated in numerous cancers including advanced stages of prostate cancer. In this study, we demonstrate that high-fat diets (HFDs) promoted pathological transformation mediated by the synergy of Src and androgen receptor in vivo. Additionally, a diet high in saturated fat significantly enhanced proliferation of Src-mediated xenograft tumors in comparison with a diet high in unsaturated fat. The saturated fatty acid palmitate, a major constituent in a HFD, significantly upregulated the biosynthesis of palmitoyl-CoA in cancer cells in vitro and in xenograft tumors in vivo. The exogenous palmitate enhanced Src-dependent mitochondrial ß-oxidation. Additionally, it elevated the amount of C16-ceramide and total saturated ceramides, increased the level of Src kinase localized in the cell membrane, and Src-mediated downstream signaling, such as the activation of mitogen-activated protein kinase and focal adhesion kinase. Our results uncover how the metabolism of dietary palmitate cooperates with elevated Src kinase in the acceleration of prostate tumor progression.


Assuntos
Palmitatos/administração & dosagem , Neoplasias da Próstata/etiologia , Quinases da Família src/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Células PC-3 , Palmitatos/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
10.
Prostate ; 79(8): 826-839, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30889629

RESUMO

BACKGROUND: Sea cucumber is a kind of nutritious echinoderm that has multiple biological activities, including antioxidant, antibacterial, and antitumor activities. However, there is no extensive study on the antitumor effect of sea cucumber extract on prostate cancer (PCa). TBL-12 is a new sea cucumber extract. In this study, we investigated the in vivo anti-PCa effect of TBL-12 and its in vitro effects on the proliferation, apoptosis, migration, and invasion of the human PCa cell lines LNCaP, 22RV1, PC-3, and DU145, and evaluated its possible mechanisms. METHODS: Cell proliferation was analyzed by cell counting kit-8 and colony formation assays. Scratch migration assay and transwell invasiveness assay were used to observe TBL-12 effect on the migration and invasion of PCa cells. Matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and enzymatic activity was determined by Western blot analysis, quantitative reverse-transcription polymerase chain reaction, and gelatin zymography. Apoptosis level was detected by flow cytometry analysis. Western blot analysis was used to analyze p38 mitogen-activated protein kinase (MAPK) and apoptosis pathways. Angiogenic array analysis was used to explore autocrine and paracrine growth factors in PCa cell lines. Xenograft tumor model was built to observe the in vivo anticancer effect. RESULTS: TBL-12 could significantly inhibit tumor growth in xenograft PCa mice in vivo, and dramatically inhibit the proliferation, colony formation, migration, and invasiveness of PCa cells in vitro (P < 0.05 and P < 0.001). The expression and enzyme activity of MMP-2 and MMP-9 were significantly suppressed by TBL-12 ( P < 0.01), and decreased phosphorylation level of p38 in PCa cells was detected ( P < 0.001). Furthermore, TBL-12 could reinforce the MMP-2/MMP-9 inhibitory effect of SB203580, a specific inhibitor of the p38 MAPK pathway ( P < 0.05). Besides, TBL-12 could induce the apoptosis of PCa cells by activating caspase-9, caspase-7, and poly(ADP-ribose) polymerase and suppressing survivin, and inhibit the secretion of angiogenin, angiopoietin-2, and vascular endothelial growth factor in PCa cells. CONCLUSIONS: Sea cucumber extract TBL-12 could suppress the proliferation and metastasis of human PCa cells by inhibiting MMP-2 and MMP-9 via blocking the p38 MAPK pathway, inducing apoptosis through intrinsic caspase apoptosis pathway and inhibiting the secretion of angiogenic factors. Our findings may be of importance and significance for the research and clinical applications of sea cucumber extract in PCa treatment.


Assuntos
Caspase 7/metabolismo , Caspase 9/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Pepinos-do-Mar/química , Extratos de Tecidos/farmacologia , Proteínas Angiogênicas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Invasividade Neoplásica , Células PC-3 , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
J Nutr ; 149(3): 381-397, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30801647

RESUMO

BACKGROUND: Human plasma and tissue lycopene concentrations are heterogeneous even when consuming controlled amounts of tomato or lycopene. OBJECTIVES: Our objective is to determine whether single nucleotide polymorphisms (SNPs) in or near known or putative carotenoid metabolism genes [ß-carotene 15,15' monooxygenase 1 (BCO1), scavenger receptor class B type 1 (SCARB1), ATP-binding cassette transporter subfamily A member 1 (ABCA1), microsomal triglyceride transfer protein (MTTP), apolipoprotein B-48, elongation of very long chain fatty acids protein 2 (ELOVL2), and ATP-binding cassette subfamily B member 1 (ABCB1), and an intergenic superoxide dismutase 2, mitochondrial-associated SNP] are predictive of plasma lycopene responses to steady state tomato juice consumption. METHODS: Secondary linear regression analyses of data from a dose-escalation study of prostate cancer patients [n = 47; mean ± SEM age: 60 ± 1 y; BMI (in kg/m2): 32 ± 1] consuming 0, 1, or 2 cans of tomato-soy juice/d (163 mL/can; 20.6 mg lycopene 1.2 mg ß-carotene/can) for 24 ± 0.7 d before prostatectomy were conducted to explore 11 SNP genotype effects on the change in plasma lycopene and plasma and prostate tissue concentrations of lycopene, ß-carotene, phytoene, and phytofluene. RESULTS: Two BCO1 SNP genotypes were significant predictors of the change in plasma lycopene, with SNP effects differing in magnitude and direction, depending on the level of juice intake (rs12934922 × diet group P = 0.02; rs6564851 × diet group P = 0.046). Further analyses suggested that plasma ß-carotene changes were predicted by BCO1 rs12934922 (P < 0.01), prostate lycopene by trending interaction and main effects of BCO1 SNPs (rs12934922 × diet group P = 0.09; rs12934922 P = 0.02; rs6564851 P = 0.053), and prostate ß-carotene by BCO1 SNP interaction and main effects (rs12934922 × diet group P = 0.01; rs12934922 P < 0.01; rs7501331 P = 0.02). CONCLUSIONS: In conclusion, SNPs in BCO1 and other genes may modulate human plasma and prostate tissue responses to dietary lycopene intake and warrant validation in larger, human controlled feeding intervention and cohort studies. Genetic variants related to carotenoid metabolism may partially explain heterogeneous human blood and tissue responses and may be critical covariates for population studies and clinical trials. This trial was registered at clinicaltrials.gov as NCT01009736.


Assuntos
Licopeno/sangue , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/dietoterapia , Proteínas de Soja , beta-Caroteno 15,15'-Mono-Oxigenase/genética , Bebidas/análise , Carotenoides/sangue , Genótipo , Humanos , Desequilíbrio de Ligação , Licopeno/metabolismo , Lycopersicon esculentum/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/enzimologia , beta Caroteno/sangue , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismo
12.
J Biol Chem ; 294(12): 4572-4582, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30718275

RESUMO

Chemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immune histochemical, chemistry, and precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin. We observed that genetic PBX1 knockdown abrogates this resistance, and further experiments revealed that PBX1 stability was modulated by the ubiquitin-proteasomal pathway. To directly probe the impact of this pathway on PBX1 activity, we screened for PBX1-specific deubiquitinases (Dubs) and found that ubiquitin-specific peptidase 9 X-linked (USP9x) interacted with and stabilized the PBX1 protein by attenuating its Lys-48-linked polyubiquitination. Moreover, the USP9x inhibitor WP1130 markedly induced PBX1 degradation and promoted PCa cell apoptosis. The results in this study indicate that PBX1 confers to PCa chemoresistance and identify USP9x as a Dub of PBX1. We concluded that targeting the USP9x/PBX1 axis could be a potential therapeutic strategy for managing advanced prostate cancer.


Assuntos
Apoptose , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Neoplasias da Próstata/patologia , Ubiquitina Tiolesterase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo
13.
Eur J Pharmacol ; 846: 1-11, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30639309

RESUMO

Auranofin (Aur) inhibits thioredoxin reductases and is also an inhibitor of 19S proteasome associated deubiquitinases, targeting USP14 and UCHL5. Androgen receptor is often over-expressed in prostate cancer (PCa) and is strongly linked to PCa growth and progression. Consequently, androgen deprivation therapy (ADT) that reduces androgen has been applied to treat androgen receptor-mediated PCa for decades. Nevertheless, most ADT treated patients experience relapse due to the development of the castration-resistant PCa. Numerous studies have shown that down-regulation of cellular androgen receptor level, including inhibiting its transcription and promoting its protein degradation, is lethal to PCa cells. Here we report that Aur arrested cell cycle progression and induced apoptosis of PCa cells. Co-inhibition of USP14 and UCHL5 with Aur facilitated the ubiquitination and degradation of androgen receptors in LNcap and 22RV1 PCa cells. Our results also show that Aur decreases the mRNA level of androgen receptors. In conclusion, our findings suggest that Aur is a promising agent for clinical translation to treat PCa.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Auranofina/farmacologia , Neoplasias da Próstata/enzimologia , Receptores Androgênicos/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Apoptose , Auranofina/uso terapêutico , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/enzimologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Clin Sci (Lond) ; 133(2): 269-286, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30683712

RESUMO

Increased PSA-based screening for prostate cancer has resulted in a growing number of diagnosed cases. However, around half of these are 'indolent', neither metastasizing nor leading to disease specific death. Treating non-progressing tumours with invasive therapies is currently regarded as unnecessary over-treatment with patients being considered for conservative regimens, such as active surveillance (AS). However, this raises both compliance and protocol issues. Great clinical benefit could accrue from a biomarker able to predict long-term patient outcome accurately at the time of biopsy and initial diagnosis. Here we delineate the translation of a laboratory discovery through to the precision development of a clinically validated, novel prognostic biomarker assay (InformMDx™). This centres on determining transcript levels for phosphodiesterase-4D7 (PDE4D7), an enzyme that breaks down cyclic AMP, a signalling molecule intimately connected with proliferation and androgen receptor function. Quantifiable detection of PDE4D7 mRNA transcripts informs on the longitudinal outcome of post-surgical disease progression. The risk of post-surgical progression increases steeply for patients with very low 'PDE4D7 scores', while risk decreases markedly for those patients with very high 'PDE4D7 scores'. Combining clinical risk variables, such as the Gleason or CAPRA (Cancer of the Prostate Risk Assessment) score, with the 'PDE4D7 score' further enhances the prognostic power of this personalized, precision assessment. Thus the 'PDE4D7 score' has the potential to define, more effectively, appropriate medical intervention/AS strategies for individual prostate cancer patients.


Assuntos
Biomarcadores Tumorais/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Neoplasias da Próstata/diagnóstico , RNA Mensageiro/genética , Animais , Progressão da Doença , Humanos , Masculino , Valor Preditivo dos Testes , Prostatectomia/efeitos adversos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Fatores de Risco , Pesquisa Médica Translacional , Resultado do Tratamento
15.
Med Mol Morphol ; 52(3): 164-172, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30631948

RESUMO

Sulfite oxidase (SUOX) is a metalloenzyme that plays a role in ATP synthesis via oxidative phosphorylation in mitochondria and has been reported to also be involved in the invasion and differentiation capacities of tumor cells. Here, we performed a clinicopathological investigation of SUOX expression in prostate cancer and discussed the usefulness of SUOX expression as a predictor of biochemical recurrence following surgical treatment in prostate cancer. This study was conducted using Tissue Micro Array specimens obtained from 97 patients who underwent radical prostatectomy at our hospital between 2007 and 2011. SUOX staining was used to evaluate cytoplasmic SUOX expression. In the high-expression group, the early biochemical recurrence was significantly more frequent than in the low-expression group (p = 0.0008). In multivariate analysis, high SUOX expression was found to serve as an independent prognostic factor of biochemical recurrence (hazard ratio = 2.33, 95% confidence interval = 1.32-4.15, p = 0.0037). In addition, Ki-67-labeling indices were significantly higher in the high-expression group than in the low-expression group (p = 0.0058). Therefore, SUOX expression may be a powerful prognostic biomarker for decision-making in postoperative follow-up after total prostatectomy and with regard to the need for relief treatment.


Assuntos
Recidiva Local de Neoplasia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/cirurgia , Sulfito Oxidase/genética , Idoso , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
16.
Med Sci Monit ; 25: 193-239, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616239

RESUMO

BACKGROUND The histone methyltransferase (HMT) family includes histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs). The role of HMT gene variants in prostate cancer remains unknown. Therefore, this study aimed to evaluate HMT gene variants in the pathogenesis and prognosis of human prostate cancer, using in vitro cell studies and bioinformatics analysis. MATERIAL AND METHODS Integrative bioinformatics analysis of the expression of 51 HMT genes in human prostate cancer was based on datasets from the Cancer Genome Atlas (TCGA). Correlation and regression analysis were used to identify critical HMTs in prostate cancer. Kaplan-Meier and the area under the receiver operating characteristics curve (AUROC) were performed to evaluate the function of the HMTs on prognosis. Gene expression and function of 22Rv1 human prostate carcinoma cells were studied. RESULTS The HMT genes identified to have a role in the pathogenesis of prostate cancer included the EZH2, SETD5, PRDM12, NSD1, SETD6, SMYD1, and the WHSC1L1 gene. The EZH2, SETD5, and SMYD1 genes were selected as a prognostic panel, with the SUV420H2 HMT gene. SETD2, NSD1, and ASH1L were identified as critical genes in the development of castration-resistant prostate cancer (CRPC), similar to mixed-lineage leukemia (MLL) complex family members. Knockdown of the SETD5 gene in 22Rv1 prostate carcinoma cells in vitro inhibited cancer cell growth and migration. CONCLUSIONS HMT gene variants may have a role in the pathogenesis of prostate cancer. Future studies may determine the role of HMT genes as prognostic biomarkers in patients with prostate cancer.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Neoplasias da Próstata/genética , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética , Variação Genética/genética , Histona Metiltransferases/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Metiltransferases/genética , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Prognóstico , Neoplasias da Próstata/enzimologia , Metiltransferases de Proteína/genética , Fatores de Transcrição/genética
17.
Urol Oncol ; 37(2): 123-129, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30522902

RESUMO

BACKGROUND: Serum cholinesterase (ChE) a serine hydrolase that catalyses the hydrolysis of esters of choline, is involved in cellular proliferation and differentiation, therefore affecting carcinogenesis. The aim of this study was to understand the prognostic role of preoperative serum ChE in patients with radiation-recurrent prostate cancer (CaP) treated with salvage radical prostatectomy (SRP). MATERIAL AND METHODS: This retrospective study included 214 patients with radiation-recurrent CaP treated with SRP from January 2007 to December 2015 at 5 academic centers. Patients were considered with abnormal/decreased ChE levels if <5 kU/l. Biochemical recurrence-free and metastases-free (MFS) survival analyses were performed. RESULTS: Median serum ChE level was 6.9 (interquartile range) 6-7.7) kU/l. Serum ChE level (<5 kU/l) was decreased in 25 (11.7%) patients. Decreased serum ChE level was associated with lower body mass index (P = 0.006) and metastasis to lymph nodes (P = 0.004). In multivariable analysis, continuous ChE was an independent predictor of MFS (hazard ratio [HR] 0.48, confidence interval [CI] 0.33-0.71, P < 0.001), overall survival (HR 0.68, CI 0.48-0.96, P = 0.03) and cancer-specific survival (HR 0.41, CI 0.2-0.84, P = 0.01). Serum ChE improved the C-index (by 2.54%) to 87.8% for prediction of overall survival and (by 3%) to 92% for prediction of MFS. CONCLUSION: Preoperative serum ChE is associated with the development of metastasis in patients with radiation-recurrent CaP who underwent SRP. The biological underpinning of this association with the biological and clinical aggressiveness of CaP needs to be further elucidated.


Assuntos
Adenocarcinoma/secundário , Colinesterases/sangue , Recidiva Local de Neoplasia/patologia , Prostatectomia/mortalidade , Neoplasias da Próstata/patologia , Terapia de Salvação , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/cirurgia , Fatores de Risco , Taxa de Sobrevida
18.
Cancer Lett ; 443: 80-90, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30472184

RESUMO

Tankyrase (TNKS) is a crucial mediator of Wnt signal transduction and has been recognized as a novel molecular target for Wnt-pathway dependent cancer. TNKS is stabilized by the ubiquitin-specific protease 25 (USP25). The effect of disruption of the interaction between TNKS and USP25 by small molecules on prostate cancer proliferation is unknown. In this study we conducted a hierarchical virtual screening with more than 200,000 compounds on the characterized structures of the USP25/TNKS-ARC5 protein complex. In silico analysis and in vitro validation revealed that a small molecule, called C44, binds to the protein-protein interaction (PPI) interface of TNKS and USP25. We show that C44 disrupts the interaction between TNKS and USP25 leading to a higher half-life of AXIN and the breakdown of -catenin protein. We also show that the selective inhibition of the TNKS-USP25 interaction by C44 significantly reduces proliferation of prostate cancer cells in vitro and in vivo. Our study reveals a new PPI inhibitor that lowers the stability of TNKS protein and inhibits Wnt pathway signaling. C44 is a promising new drug for the treatment of Wnt-pathway dependent prostate cancer.


Assuntos
Inibidores Enzimáticos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/administração & dosagem , Tanquirases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Neoplasias da Próstata/enzimologia , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tanquirases/química , Tanquirases/metabolismo , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Transl Res ; 203: 49-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30287243

RESUMO

Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors; however, little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa). ALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastases. It was correlated to clinico-pathologic parameters, patients' outcome, and selected proteins (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin). ALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced T stage (P = 0.009), higher Gleason score (P = 0.016), shorter time to biochemical recurrence (TBR P = 0.010) and CK14 expression (P = 0.023). Stromal cell ALDH1 expression correlated to lower T stage (P = 0.008) and Gleason score (P = 0.016), N0 stage (P = 0.017), and longer TBR (P = 0.017). It occurred to be an independent predictor of good prognosis in the subgroup of d'Amico high-risk patients (multivariate analysis, P = 0.050). ALDH1-positive stromal cells were found in tumors characterized frequently by CK8/18 (P = 0.033) or EpCAM expression (P < 0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (P = 0.003). ALDH1-positive tumor and stromal cells were detected in 33% and 41% of hormone naive lymph node metastases (n = 63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n = 21), respectively. We have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with epithelial phenotype of primary PCa, improved clinical outcome, and is less frequent in PCa metastases.


Assuntos
Isoenzimas/metabolismo , Neoplasias da Próstata/enzimologia , Retinal Desidrogenase/metabolismo , Células Estromais/metabolismo , Células Cultivadas , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Retinal Desidrogenase/genética
20.
Biochem Biophys Res Commun ; 508(3): 973-979, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30551877

RESUMO

XAF1 is a tumor suppressor gene with low or absent expression in cancer. Since transcriptional reactivation or ectopic-mediated expression of XAF1 inhibits tumor growth, it is of great interest to elucidate the molecular mechanisms leading to XAF1 silencing. YY1 is a transcription factor that acts as a repressor or an activator to modulate several cancer-associated cellular processes. Both YY1 and XAF1 have key roles in prostate cancer (PCa) progression and are associated with worse clinical outcomes. To assess whether YY1 regulates the transcriptional activation of the XAF1 gene, we performed gene-reporter assays coupled with site-directed mutagenesis, which showed that YY1 is able to mediate XAF1 silencing. Concordantly, ChIP-qPCR assays showed that YY1 interacts with the XAF1 promoter in PC3 cells that lacks XAF1 expression. This association was lost after exposure to epigenetic modulators that induce XAF1 expression. Further supporting the YY1's repressive role, we found transcriptional reactivation of the XAF1 gene by YY1 downregulation. As expected by previous reports showing that HDAC1 is needed for YY1-mediated repressive actions, we observed XAF1 re-expression after either inhibition or downregulation of the HDAC1 gene. Finally, expression data retrieved from the TCGA consortium showed that PCa samples presented lower XAF1 and higher HDAC expression levels than normal tissues. Thus, our results support a model in which YY1 is able to silence tumor suppressor genes such as XAF1 through HDAC1 in PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Fator de Transcrição YY1/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Masculino , Proteínas de Neoplasias/biossíntese , Regiões Promotoras Genéticas , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Fator de Transcrição YY1/genética
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