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1.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207168

RESUMO

Xanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer, and nonsolid tumor derived cancer (Jurkat) cell lines. The effect of xanthone 1 on macrophage functions was also evaluated. The effect of xanthone 1-conditioned THP-1 human macrophage supernatants on the metabolic viability of cervical and prostate cancer cell lines was determined along with its interference with cytokine expression characteristic of M1 profile (IL-1 ≤ ß; TNF-α) or M2 profile (IL-10; TGF-ß) (PCR and ELISA). Nitric oxide (NO) production by murine RAW264.7 macrophages was quantified by Griess reaction. Xanthone 1 (20 µM) strongly inhibited the metabolic activity of the cell lines and was significantly more active against prostate cell lines compared to HeLa (p < 0.05). Jurkat was the cell most sensitive to the effect of xanthone 1. Compound 1-conditioned IL-4-stimulated THP-1 macrophage supernatants significantly (p < 0.05) inhibited the metabolic activity of HeLa, LNCaP, and PC-3. Xanthone 1 did not significantly affect the expression of cytokines by THP-1 macrophages. The inhibiting effect of compound 1 observed on the production of NO by RAW 264.7 macrophages was moderate. In conclusion, 1-carbaldehyde-3,4-dimethoxyxanthone (1) decreases the metabolic activity of cancer cells and seems to be able to modulate macrophage functions.


Assuntos
Antineoplásicos/farmacologia , Macrófagos/efeitos dos fármacos , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Xantonas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Células HeLa , Papillomavirus Humano 18/patogenicidade , Humanos , Células Jurkat , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células PC-3 , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Células RAW 264.7 , Células THP-1 , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
2.
Int J Nanomedicine ; 16: 4391-4407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234433

RESUMO

Background: Gold nanocages have been widely used as multifunctional platforms for drug and gene delivery, as well as photothermal agents for cancer therapy. However, their potential as gene delivery systems for cancer treatment has been reported in combination with chemotherapeutics and photothermal therapy, but not in isolation so far. The purpose of this work was to investigate whether the conjugation of gold nanocages with the cancer targeting ligand lactoferrin, polyethylene glycol and polyethylenimine could lead to enhanced transfection efficiency on prostate cancer cells in vitro, without assistance of external stimulation. Methods: Novel lactoferrin-bearing gold nanocages conjugated to polyethylenimine and polyethylene glycol have been synthesized and characterized. Their transfection efficacy and cytotoxicity were assessed on PC-3 prostate cancer cell line following complexation with a plasmid DNA. Results: Lactoferrin-bearing gold nanocages, alone or conjugated with polyethylenimine and polyethylene glycol, were able to condense DNA at conjugate:DNA weight ratios 5:1 and higher. Among all gold conjugates, the highest gene expression was obtained following treatment with gold complex conjugated with polyethylenimine and lactoferrin, at weight ratio 40:1, which was 1.71-fold higher than with polyethylenimine. This might be due to the increased DNA cellular uptake observed with this conjugate, by up to 8.65-fold in comparison with naked DNA. Conclusion: Lactoferrin-bearing gold nanocages conjugates are highly promising gene delivery systems to prostate cancer cells.


Assuntos
Portadores de Fármacos/química , Técnicas de Transferência de Genes , Ouro/química , Lactoferrina/química , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , DNA/administração & dosagem , DNA/química , DNA/genética , Terapia Genética , Humanos , Masculino , Plasmídeos/genética , Polietilenoglicóis/química , Polietilenoimina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Transfecção
3.
Anticancer Res ; 41(7): 3271-3279, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230121

RESUMO

BACKGROUND/AIM: Androgen receptor (AR) degradation is the primary regulator of androgen receptor activity. This study was designed to investigate the influence of the proteasome on AR protein stability after enzalutamide (Enz) treatment. MATERIALS AND METHODS: Cell counting after treatment was utilized to assess the effect of Enz on cell proliferation. Changes in mRNA levels were evaluated using reverse transcription-polymerase chain reaction (RT-PCR). Proteasome activity was assessed by measurement of the chymotrypsin-like activity of the beta-5 subunit of the proteasome. Changes in protein levels after treatment with Enz, MG132 (MG), bortezomib (Bor), or their combination were assessed using western blot analysis. RESULTS: Treatment with Enz led to a significant reduction of cell proliferation and AR protein levels. However, AR mRNA levels were unchanged. Inhibition of proteasome activity by MG counteracts the Enz-mediated AR degradation transiently, whereas Bor showed no inhibition of the Enz-mediated AR degradation. CONCLUSION: Enz-mediated change in AR stability as an early and essential event after treatment was shown. However, investigations of the ubiquitin/proteasome system indicate involvement of several proteases in the Enz-mediated AR degradation process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/farmacologia , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Leupeptinas/farmacologia , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , RNA Mensageiro/metabolismo
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(6): 953-959, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34238751

RESUMO

OBJECTIVE: To investigate the apoptosis- inducing effect of fucoxanthin in human prostate cancer PC-3 cells and the underlying mechanism. OBJECTIVE: The viability and apoptosis of PC-3 cells treated with fucoxanthin were analyzed using commercial kits, and the mitochondrial membrane potential, mitochondrial morphology and mitochondrial superoxide were detected using fluorescence probe staining. The contents of ATP, H2O2, malondialdehyde (MDA), superoxide and the total antioxidant capacity of PC-3 cells were determined. The protein expressions of Bcl-2, Bax and cytochrome c were detected with Western blotting, and the activity of caspase-9 and caspase- 3/7 was detected using corresponding kits. OBJECTIVE: Fucoxanthin significantly inhibited the viability of PC-3 cells in a time- and dose-dependent manner, and dose-dependently induced apoptosis of the cells (P < 0.05). Fucoxanthin-treated PC-3 cells showed significantly decreased mitochondrial membrane potential, mitochondrial fragmentation and increased superoxide level in the mitochondria (P < 0.05), and these effects of fucoxanthin were dose- dependent. Fucoxanthin dose-dependently decreased ATP level and the total antioxidant capacity of PC-3 cells, increased the contents of H2O2, MDA and superoxide (all P < 0.05), enhanced the protein expressions of Bax and cytochrome c in the cytoplasm, and lowered the protein expressions of Bcl-2 and cytochromes in the mitochondria (P < 0.05). OBJECTIVE: Fucoxanthin induces apoptosis of PC-3 cells by triggering mitochondrial dysfunction to cause oxidative stress and by activating mitochondria-mediated apoptotic signaling pathways, suggesting its potential in prostate cancer treatment.


Assuntos
Peróxido de Hidrogênio , Neoplasias da Próstata , Apoptose , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Estresse Oxidativo , Células PC-3 , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Xantofilas , Proteína X Associada a bcl-2/metabolismo
5.
Nat Commun ; 12(1): 3372, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099734

RESUMO

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.


Assuntos
Adenocarcinoma/genética , Carcinoma Neuroendócrino/genética , Regulação Neoplásica da Expressão Gênica , Próstata/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Adenocarcinoma/metabolismo , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Técnicas de Cultura de Órgãos/métodos , Prognóstico , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
6.
Aging (Albany NY) ; 13(12): 16316-16340, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34148031

RESUMO

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.


Assuntos
Afro-Americanos , Antineoplásicos/metabolismo , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Neoplasias da Próstata/metabolismo , Área Sob a Curva , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Epigenoma , Grupos Étnicos , Genômica , Humanos , Concentração Inibidora 50 , Masculino , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Transcriptoma/genética , Resultado do Tratamento
7.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069970

RESUMO

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression.


Assuntos
Cateninas/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transporte Ativo do Núcleo Celular , Sítios de Ligação/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/química , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Ligantes , Masculino , Modelos Biológicos , Mutagênese Sítio-Dirigida , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Células PC-3 , Fosforilação , Neoplasias da Próstata/genética , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/química , Transdução de Sinais , Treonina/química
8.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069262

RESUMO

Aberrant glycosylation has long been known to be associated with cancer, since it is involved in key mechanisms such as tumour onset, development and progression. This review will focus on protein glycosylation studies in cells, tissue, urine and serum in the context of prostate cancer. A dedicated section will cover the glycoforms of prostate specific antigen, the molecule that, despite some important limitations, is routinely tested for helping prostate cancer diagnosis. Our aim is to provide readers with an overview of mass spectrometry-based glycoproteomics of prostate cancer. From this perspective, the first part of this review will illustrate the main strategies for glycopeptide enrichment and mass spectrometric analysis. The molecular information obtained by glycoproteomic analysis performed by mass spectrometry has led to new insights into the mechanism linking aberrant glycosylation to cancer cell proliferation, migration and immunoescape.


Assuntos
Biomarcadores Tumorais/análise , Espectrometria de Massas/métodos , Neoplasias da Próstata/metabolismo , Proteômica/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/urina , Glicosilação , Humanos , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/urina
9.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074045

RESUMO

In addition to its well-known role as an energy repository, adipose tissue is one of the largest endocrine organs in the organism due to its ability to synthesize and release different bioactive molecules. Two main types of adipose tissue have been described, namely white adipose tissue (WAT) with a classical energy storage function, and brown adipose tissue (BAT) with thermogenic activity. The prostate, an exocrine gland present in the reproductive system of most mammals, is surrounded by periprostatic adipose tissue (PPAT) that contributes to maintaining glandular homeostasis in conjunction with other cell types of the microenvironment. In pathological conditions such as the development and progression of prostate cancer, adipose tissue plays a key role through paracrine and endocrine signaling. In this context, the role of WAT has been thoroughly studied. However, the influence of BAT on prostate tumor development and progression is unclear and has received much less attention. This review tries to bring an update on the role of different factors released by WAT which may participate in the initiation, progression and metastasis, as well as to compile the available information on BAT to discuss and open a new field of knowledge about the possible protective role of BAT in prostate cancer.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Neoplasias da Próstata/metabolismo , Microambiente Tumoral , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Citocinas/metabolismo , Progressão da Doença , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/patologia
10.
Ecotoxicol Environ Saf ; 220: 112376, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051661

RESUMO

Previous studies suggest that cadmium (Cd) is one of the causative factors of prostate cancer (PCa), but the effect of chronic Cd exposure on PCa progression remains unclear. Besides, whether long noncoding RNAs (lncRNAs) are involved in the regulation of prolonged exposure to Cd in PCa needs to be elucidated. In the present study, we found that the serum concentration of Cd in PCa patients was positively correlated with the Gleason score and tumor-node-metastasis (TNM) classification. To simulate chronic Cd exposure in PCa, we subjected PC3 and DU145 cells to long-term, low-dose Cd exposure and further examined tumor behavior. Functional studies identified that chronic Cd exposure promoted cell growth and ferroptosis resistance in vitro and in vivo. Furthermore, we found that lncRNA OIP5-AS1 expression was greatly elevated in PC3 and DU145 cells upon chronic Cd exposure. Dysregulation of OIP5-AS1 expression mediated cell growth and Cd-induced ferroptosis. Mechanistically, we demonstrated that OIP5-AS1 served as an endogenous sponge of miR-128-3p to regulate the expression of SLC7A11, a surrogate marker of ferroptosis. Moreover, miR-128-3p decreased cell viability by enhancing ferroptosis. Taken together, our data indicate that lncRNA OIP5-AS1 promotes PCa progression and ferroptosis resistance through miR-128-3p/SLC7A11 signaling.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Ferroptose/efeitos dos fármacos , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cádmio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Poluentes Ambientais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Transdução de Sinais
11.
Cell Prolif ; 54(7): e13056, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34021647

RESUMO

OBJECTIVES: In contrast to extensive studies on bone metastasis in advanced prostate cancer (PCa), liver metastasis has been under-researched so far. In order to decipher molecular and cellular mechanisms underpinning liver metastasis of advanced PCa, we develop a rapid and immune sufficient mouse model for liver metastasis of PCa via orthotopic injection of organoids from PbCre+ ; rb1f/f ;p53f/f mice. MATERIALS AND METHODS: PbCre+ ;rb1f/f ;p53f/f and PbCre+ ;ptenf/f ;p53f/f mice were used to generate PCa organoid cultures in vitro. Immune sufficient liver metastasis models were established via orthotopic transplantation of organoids into the prostate of C57BL/6 mice. Immunofluorescent and immunohistochemical staining were performed to characterize the lineage profile in primary tumour and organoid-derived tumour (ODT). The growth of niche-labelling reporter infected ODT can be visualized by bioluminescent imaging system. Immune cells that communicated with tumour cells in the liver metastatic niche were determined by flow cytometry. RESULTS: A PCa liver metastasis model with full penetrance is established in immune-intact mouse. This model reconstitutes the histological and lineage features of original tumours and reveals dynamic tumour-immune cell communication in liver metastatic foci. Our results suggest that a lack of CD8+ T cell and an enrichment of CD163+ M2-like macrophage as well as PD1+ CD4+ T cell contribute to an immuno-suppressive microenvironment of PCa liver metastasis. CONCLUSIONS: Our model can be served as a reliable tool for analysis of the molecular pathogenesis and tumour-immune cell crosstalk in liver metastasis of PCa, and might be used as a valuable in vivo model for therapy development.


Assuntos
Neoplasias Hepáticas/patologia , Neoplasias da Próstata/patologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular , Modelos Animais de Doenças , Neoplasias Hepáticas/secundário , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
12.
Mol Biol Rep ; 48(4): 3567-3578, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33948856

RESUMO

Cancer stem cells (CSCs) are a unique population that has been linked to drug resistance and metastasis and recurrence of prostate cancer. The sonic hedgehog (SHH) signal regulates stem cells in normal prostate epithelium by affecting cell behavior, survival, proliferation, and maintenance. Aberrant SHH pathway activation leads to an unsuitable expansion of stem cell lineages in the prostate epithelium and the transformation of prostate CSCs (PCSCs). Zoledronic acid (ZOL), one of the third-generation bisphosphonates, effectively prevented bone metastasis and treated advanced prostate cancer despite androgen deprivation therapy. Despite strong evidence for the involvement of the SHH in human PCSCs survival and drug resistance, the roles of SHH in the PCSCs-related resistance to ZOL remain to be fully elucidated. The present study aimed to investigate the role of the SHH pathway in ZOL resistance of PCSCs in 2D and three 3D cell culture conditions. For this purpose, we isolated CD133high/ CD44high PCSCs using a flow cytometer. Following ZOL treatment, mRNA and protein expressions of the components of the SHH signaling pathway in PCSCs and non-CSCs were analyzed using qRT-PCR and Immunofluorescence staining, respectively. Our finding suggested that SHH signaling may be activated by different mechanisms that lead to avoidance of the inhibition effect of ZOL. Thereby, SHH pathways may be associated with the resistance to ZOL developed by prostate CSCs. Inhibition of CSCs-related SHH signaling along with ZOL treatment should be considered to achieve improvement in survival or delayed treatment failure and prevention of the CSCs-related drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno AC133/genética , Antígeno AC133/metabolismo , Antineoplásicos/toxicidade , Conservadores da Densidade Óssea/toxicidade , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Masculino , Transdução de Sinais , Ácido Zoledrônico/toxicidade
13.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946990

RESUMO

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.


Assuntos
Processamento de Proteína Pós-Traducional/fisiologia , Transdução de Sinais/fisiologia , Proteases Específicas de Ubiquitina/fisiologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/fisiologia , Complexo do Signalossomo COP9/fisiologia , Humanos , Imunidade Inata , Masculino , Camundongos , NF-kappa B/metabolismo , Neoplasias da Próstata/metabolismo , Domínios Proteicos , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Precursores de RNA/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Proteases Específicas de Ubiquitina/química , Proteases Específicas de Ubiquitina/genética , Ubiquitinação , Via de Sinalização Wnt/fisiologia , Proteínas de Xenopus/metabolismo
14.
Clin Adv Hematol Oncol ; 19(4): 228-240, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33989272

RESUMO

The androgen signaling axis has been the main therapeutic target in the management of advanced prostate cancer for several decades. Over the past years, significant advances have been made in terms of a better understanding the androgen receptor (AR) pathway and mechanisms of castration resistance, along with the development of more potent AR-targeted therapies. New drugs, such as abiraterone, enzalutamide, apalutamide, and darolutamide, have been approved for castration-resistant prostate cancer and also have demonstrated an overall survival benefit in the castration-sensitive state. Despite these major advances, the majority of patients eventually present with disease progression and a rise in prostate-specific antigen, reflecting a continuous dependence of disease on the AR pathway. In this setting, a number of AR-related mechanisms of resistance have been described, and novel strategies to overcome them are an important unmet need. In this manuscript, we review the most promising strategies to target the AR pathway in prostate cancer, including bromodomain and extraterminal (BET)/bromodomain inhibitors, CREB-binding protein/p300 inhibitors, N-terminal domain inhibitors, proteolysis-targeting chimeras, and AR-targeting vaccines. Another interesting and disruptive approach to targeting the AR and potentially reversing resistance to second-generation AR antagonists is the cyclic administration of high-dose testosterone, known as bipolar androgen therapy, which is currently being explored in multiple ongoing trials.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/farmacologia , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Testosterona/farmacologia , Testosterona/uso terapêutico
15.
Nat Commun ; 12(1): 2705, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976187

RESUMO

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/genética , Processamento de Proteína Pós-Traducional , Receptores Androgênicos/genética , ADP-Ribosilação/efeitos dos fármacos , Adenocarcinoma , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , Metribolona/farmacologia , Proteínas de Neoplasias/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise de Sobrevida
16.
Life Sci ; 278: 119554, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932444

RESUMO

AIMS: Chemoresistance remains a persistent challenge in advanced prostate cancer therapy. Probenecid reportedly inhibits multiple drug-efflux transporters; hence, it can be employed as a potential sensitizer for chemotherapy. In the present study, we evaluated the effects of probenecid on three-dimensional (3D)-cultures of prostate cancer cells. MAIN METHODS: Prostate cancer cell lines, 22Rv1 and PC-3 were cultured as multicellular tumor spheroids. The effects of probenecid were evaluated using the MTT assay for viability, microscopy for spheroid size, and soft agar colony formation assay for anchorage-independent growth. KEY FINDINGS: The 3D-cultured 22Rv1 cells were less sensitive to cisplatin and doxorubicin than two-dimensional (2D) cell culture. Co-administration of probenecid at a low (100 or 300 µM), but not high (500 µM), concentration increased the sensitivity to cisplatin or doxorubicin in 22Rv1 spheroids. Probenecid increased the expression of ABCG2, a multidrug resistance transporter, in a dose-dependent manner. Furthermore, treatment with probenecid alone reduced the growth of 22Rv1 spheroids. Conversely, probenecid inhibited spheroid compaction rather than growth inhibition in 3D-cultured PC-3 cells. Moreover, probenecid inhibited colony formation of 22Rv1 and PC-3 cells in soft agar, as well as downregulated focal adhesion kinase (FAK), a crucial factor in anchorage-independent growth. SIGNIFICANCE: In 3D-cultured prostate cancer cells, probenecid demonstrated pleiotropic effects such as chemosensitization, growth suppression, inhibition of spheroid compaction, and suppression of anchorage-independent growth. Elucidating the detailed mechanism underlying these probenecid actions could result in the identification of novel therapeutic targets toward the advanced prostate cancer.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Probenecid/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
17.
Biomed Res Int ; 2021: 5515961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996996

RESUMO

Objective: The aim of the study was to investigate the antiprostate cancer effects and mechanism of ineupatolide (T-21), a natural product isolated from the Compositae plant Carpesium cernuum L., on PC-3 human prostate cancer cells. Methods: The effect of T-21 on the proliferation of PC-3 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell migration, and invasion experiments; the morphology of cell apoptosis was observed by Hoechst-propidium iodide staining; the effects of T-21 on PC-3 cell apoptosis and the cell cycle were evaluated by flow cytometry; and the effect of T-21 on the expression levels of phosphorylated protein kinase B (p-AKT), AKT, X-linked inhibitor of apoptosis protein (xlAP), procaspase-3, and poly (ADP-ribose) polymerase (PARP) in PC-3 cells was measured by western blotting. Results: T-21 significantly inhibited the proliferation of cells, and its half-maximal inhibitory concentrations at 12, 24, and 48 h were 38.46 ± 1.01, 24.63 ± 0.70, and 7.36 ± 0.58 µM, respectively. T-21 may promote cell apoptosis in a concentration-dependent manner and block the cell cycle in the G2 and S phases. In addition, T-21 significantly reduced the protein expression levels of p-AKT, AKT, xlAP, procaspase-3, and PARP. Conclusion: T-21 exhibits antiproliferation effects on PC-3 cells by promoting apoptosis and arresting the cell cycle in the G2 and S phases. The possible mechanism underlying its potential therapeutic effects against prostate cancer is related to the AKT/xlAP pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Compostos Fitoquímicos/farmacologia , Neoplasias da Próstata/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Células PC-3 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
18.
Toxicol Lett ; 348: 50-58, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34052307

RESUMO

Antimony is a common environmental contaminant that causes biological toxicity in exposed populations worldwide. Previous studies have revealed that antimony promotes prostate cancer growth by stabilizing the c-Myc protein and mimicking androgen activity. However, the role of lncRNAs in the regulation of antimony-induced carcinogenesis remains unknown, and the precise mechanisms need to be explored. In the present study, we found that chronic exposure to antimony promoted cell growth and lipid metabolic disequilibrium in prostate cancer. Mechanistically, we identified a long noncoding RNA molecule, PCA3, that was substantially upregulated in LNCaP cells in response to long-term antimony exposure. Functional studies indicated that abnormal PCA3 expression modulated antimony-induced proliferation and cellular triglyceride and cholesterol levels. In addition, PCA3 levels were found to be inversely correlated with MIR-132-3 P levels by acting as a decoy for MIR-132-3P. Besides, SREBP1 directly interacted with MIR-132-3 P to increase cell growth and disrupt lipid metabolism by targeting its 3'UTR regions. Taken together, our results revealed that lncRNA PCA3 promotes antimony-induced lipid metabolic disorder in prostate cancer by targeting MIR-132-3 P/SREBP1 signaling.


Assuntos
Antígenos de Neoplasias/fisiologia , Antimônio/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/fisiologia , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/fisiologia
19.
J Cancer Res Clin Oncol ; 147(7): 1957-1971, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33811272

RESUMO

PURPOSE: Human tau is a highly dynamic, multifunctional protein expressed in different isoforms and conformers, known to modulate microtubule turnover. Tau oligomers are considered pathologic forms of the protein able to initiate specific protein accumulation diseases, called tauopathies. In our study, we investigated the potential association between autophagy and tau oligomers accumulation and its role in the response of prostate cancer cells to docetaxel. METHODS: We evaluated in vitro the expression of tau oligomers in prostate cancer cell lines, PC3 and DU145, in presence of autophagy inhibitors and investigated the role of tau oligomers accumulation in resistance to docetaxel treatment. RESULTS: Tau protein was basally expressed in prostate cancer lines as several monomeric and oligomeric forms. The pharmacologic inhibition of autophagy induced in cancer cells the accumulation of tau protein, with a prevalent expression of oligomeric forms. Immunofluorescence analysis of untreated cells revealed that tau was visible mainly in dividing cells where it was localized on the mitotic spindle. Inhibition of autophagy determined an evident upregulation of tau signal in dividing cells and the presence of aberrant monoastral mitotic spindles. The accumulation of tau oligomers was associated with DNA DSB and increased cytotoxic effect by docetaxel. CONCLUSIONS: Our data indicate that autophagy could exert a promoting role in cancer growth and during chemotherapy facilitating degradation of tau protein and thus blocking the antimitotic effect of accumulated tau oligomers. Thus, therapeutic strategies aimed at stimulating tau oligomers formation, such as autophagy inhibition, could be an effective adjuvant in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Autofagia , Docetaxel/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/tratamento farmacológico , Multimerização Proteica , Proteínas tau/química , Apoptose , Proliferação de Células , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas
20.
Int J Mol Sci ; 22(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916521

RESUMO

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5-15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.


Assuntos
Mutação em Linhagem Germinativa , Terapia de Alvo Molecular , Proteínas de Neoplasias , Neoplasias da Próstata , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle
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