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Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.
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Antineoplásicos , Productos Biológicos , Neoplasias de la Mama , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de SeñalRESUMEN
Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.
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Antozoos/química , Carcinoma Ductal Pancreático , Citotoxinas , Diterpenos , Janus Quinasa 2/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacología , Diterpenos/química , Diterpenos/farmacología , Neoplasias PancreáticasRESUMEN
Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.
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Médula Ósea/patología , Regulación de la Expresión Génica/genética , Hidroxibutirato Deshidrogenasa/fisiología , Leucemia Mieloide Aguda/enzimología , Síndromes Mielodisplásicos/enzimología , Preleucemia/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Médula Ósea/metabolismo , Puntos de Control del Ciclo Celular/genética , Diferenciación Celular/genética , Femenino , Ferritinas/sangre , Regulación Leucémica de la Expresión Génica , Humanos , Hidroxibutirato Deshidrogenasa/biosíntesis , Hidroxibutirato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Lipocalina 2/biosíntesis , Lipocalina 2/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Preleucemia/genética , Preleucemia/patología , Pronóstico , Supervivencia sin Progresión , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , ARN Interferente Pequeño/genética , Células THP-1 , Adulto JovenRESUMEN
BACKGROUND & AIMS: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation. METHODS: We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in human pancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays. RESULTS: NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell transdifferentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1. CONCLUSIONS: In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.
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Carcinoma Ductal Pancreático/genética , Plasticidad de la Célula/genética , Transformación Celular Neoplásica/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Regulación de la Expresión Génica , Factores de Transcripción NFATC/genética , Neoplasias Pancreáticas/genética , Regeneración/genética , Células Acinares/fisiología , Animales , Carcinoma Ductal Pancreático/química , Proliferación Celular/genética , Transdiferenciación Celular/genética , Ceruletida , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteína Potenciadora del Homólogo Zeste 2/análisis , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Silenciador del Gen , Histonas/metabolismo , Humanos , Metilación , Ratones , Factores de Transcripción NFATC/análisis , Factores de Transcripción NFATC/metabolismo , Páncreas/fisiología , Neoplasias Pancreáticas/química , Pancreatitis Crónica/inducido químicamente , Pancreatitis Crónica/fisiopatología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal/genética , Transcripción GenéticaRESUMEN
Silk fibroin (SF) is a protein with bulky hydrophobic domains and can be easily purified as sericin-free silk-based biomaterial. Silk fibroin modified chitosan nanoparticle (SF-CSNP), a biocompatible material, has been widely used as a potential drug delivery system. Our current investigation studied the bio-effects of the SF-CSNP uptake by liver cells. In this experiment, the characterizations of SF-CSNPs were measured by particle size analysis and protein assay. The average size of the SF-CSNP was 311.9 ± 10.7 nm, and the average zeta potential was +13.33 ± 0.3 mV. The SF coating on the SF-CSNP was 6.27 ± 0.17 µg/mL. Moreover, using proteomic approaches, several proteins involved in the ubiquitin proteasome pathway were identified by analysis of differential protein expressions of HepG2 cell uptake the SF-CSNP. Our experimental results have demonstrated that the SF-CSNP may be involved in liver cancer cell survival and proliferation.
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Quitosano/metabolismo , Portadores de Fármacos/metabolismo , Fibroínas/metabolismo , Nanopartículas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Materiales Biocompatibles/metabolismo , Línea Celular , Células Hep G2 , Humanos , Proteómica , Transducción de SeñalRESUMEN
BACKGROUND: The relevance of recurrent molecular abnormalities in cytogenetically normal (CN) acute myeloid leukemia (AML) was recently acknowledged by the inclusion of molecular markers such as NPM1, FLT3, and CEBPA as a complement to cytogenetic information within both the World Health Organization and the European Leukemia Net classifications. Mitochondrial metabolism is different in cancer and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2, 3-DHBA during enterobactin biosynthesis and participates in 24p3 (LCN2)-mediated iron transport and apoptosis. RESULTS: We observed that BDH2 expression is an independent poor prognostic factor for CN-AML, with an anti-apoptotic role. Patients with high BDH2 expression have relatively shorter overall survival (P = 0.007) and a low complete response rate (P = 0.032). BDH2-knockdown (BDH2-KD) in THP1 and HL60 cells increased the apoptosis rate under reactive oxygen species stimulation. Decrease inducible survivin, a member of the inhibitors of apoptosis family, but not members of the Bcl-2 family, induced apoptosis via a caspase-3-independent pathway upon BDH2-KD. CONCLUSIONS: BDH2 is a novel independent poor prognostic marker for CN-AML, with the role of anti-apoptosis, through surviving.
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Regulación Leucémica de la Expresión Génica , Hidroxibutirato Deshidrogenasa/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Línea Celular , China/epidemiología , Femenino , Técnicas de Silenciamiento del Gen , Células HL-60 , Humanos , Hidroxibutirato Deshidrogenasa/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Nucleofosmina , Pronóstico , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Survivin , Adulto JovenRESUMEN
Methyl antcinate A (MAA) is an ergostane-type triterpenoid extracted from the fruiting bodies of Antrodia camphorate that has been reported to be a cytotoxic agent towards some types of cancer cells, such as oral cancer and liver cancer. Cancer stem cells (CSCs) are a particular population within cancer cells which are responsible for tumor initiation, drug resistance and metastasis and targeting CSCs is an emerging area in cancer therapy. In this study, we examine the effect of MAA on cancer stem-like cells in the MCF7 human breast cancer cell line. Although MAA displayed very low cytotoxic effect towards MCF7 under normal culture conditions, it did show good inhibitory effects on the self-renewal capability which was examined by mammosphere culture including primary and secondary sphere. MAA also inhibited cell migration ability of MCF7 sphere cells. By western blot analysis, MAA was shown to suppress the expression of heat shock protein 27 and increase the expression of IkBα and p53. In conclusion, our data demonstrate that MAA has anti-CSC activity and is worthy of future development of potent anticancer agents.
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Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Triterpenos/farmacología , Antineoplásicos/toxicidad , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Células MCF-7 , Esferoides Celulares , Triterpenos/toxicidad , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The role of miRNAs in cancer and their possible function as therapeutic agents are interesting and needed further investigation. The miR-26a-5p had been demonstrated as a tumor suppressor in various cancers. However, the importance of miR-26a-5p regulation in upper tract urothelial carcinoma (UTUC) remains unclear. Here, we aimed to explore the miR-26a-5p expression in UTUC tissues and to identify its regulatory targets and signal network involved in UTUC tumorigenesis. The miR-26a-5p expression was validated by quantitative real-time polymerase chain reaction (qPCR) using renal pelvis tissue samples from 22 patients who were diagnosed with UTUC and 64 cases of renal pelvis tissue microarray using in situ hybridization staining. BFTC-909 UTUC cells were used to examine the effects of miR-26a-5p genetic delivery on proliferation, migration and expression of epithelial-to-mesenchymal transition (EMT) markers. MiR-26a-5p was significantly down-regulated in UTUC tumors compared to adjacent normal tissue and was decreased with histological grades. Moreover, restoration of miR-26a-5p showed inhibition effects on proliferation and migration of BFTC-909 cells. In addition, miR-26a-5p delivery regulated the EMT marker expression and inhibited WNT5A/ß-catenin signaling and expression of downstream molecules including NF-κB and MMP-9 in BFTC-909 cells. This study demonstrated that miR-26a-5p restoration may reverse EMT process and regulate WNT5A/ß-catenin signaling in UTUC cells. Further studies warranted to explore the potential roles in biomarkers for diagnostics and prognosis, as well as novel therapeutics targets for UTUC treatment.
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Carcinoma de Células Transicionales , MicroARNs , Neoplasias de la Vejiga Urinaria , Femenino , Humanos , Masculino , MicroARNs/genética , Transducción de Señal , Proteína Wnt-5a/genética , beta CateninaRESUMEN
This systematic review and meta-analysis aimed to explore the association between the Mediterranean dietary pattern and inflammation in older adults. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A search of the literature was conducted up to June 2020 in 7 electronic databases, namely PubMed, Embase, Web of Science, Scopus, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ProQuest. The Joanna Briggs Institute Critical Appraisal Checklists and the Newcastle-Ottawa Scale were used to assess the methodological quality. The overall standardized mean difference (SMD) and 95% CIs were estimated in random-effects meta-analyses. Thirteen studies were identified as having acceptable quality and were included in this systematic review: 3 randomized controlled trials (RCTs), 1 quasi-experimental study, 1 cohort study, and 8 cross-sectional studies. The circulating C-reactive protein (CRP) concentration was the most common inflammation indicator used. Results of the meta-analysis on 5 cross-sectional studies revealed a significant inverse association between the Mediterranean dietary pattern and inflammation as assessed by CRP (SMD = -0.26; 95% CI: -0.41, -0.11; P < 0.001). Other studies that investigated a variety of inflammation indicators other than CRP showed mixed results with regard to the relation between the Mediterranean dietary pattern and inflammation in older adults. Our findings suggest that the Mediterranean dietary pattern may be associated with lower inflammation in older adults. However, more long-term RCTs are required to demonstrate the effects of the Mediterranean dietary pattern on multiple inflammation parameters in older adults. The study has been registered on PROSPERO (#CRD42020140145).
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Dieta , Inflamación , Anciano , Humanos , Proteína C-Reactiva , Estudios Transversales , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Melatonin, produced by the pineal gland, is known for its antioxidant, oncostatic, and anti-inflammatory properties. However, studies on serum melatonin levels in different cancer types have yielded conflicting results, and little is known about the clinical significance of serum melatonin in oral squamous cell carcinoma (OSCC) in the Southern Asian population. Therefore, we explored its role in OSCC in this study. METHODS: A total of 67 male OSCC patients and 78 healthy controls were enrolled in this case-control study. The serum levels of melatonin were determined by enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. RESULTS: The serum melatonin levels were significantly lower in OSCC patients compared with healthy controls (mean ± standard deviation, 15.0 ± 4.6 vs. 18.5 ± 11.8 pg/mL, p = 0.02). In the subgroup of age less than 55 years (mean age of OSCC), OSCC patients had a significantly decreased melatonin level than healthy controls (mean melatonin, 15.7 ± 12.6 vs. 20.8 ± 3.9 pg/mL, p = 0.02). Decreased serum melatonin (odds ratio (OR): 0.95, 95%CI: 0.91-0.99), alcohol consumption (OR: 29.02, 95%CI: 11.68-72.16), betel quid chewing (OR:136.44, 95%CI: 39.17-475.27), and cigarette smoking (OR:29.48, 95%CI: 11.06-78.60) all increased the risk of OSCC under univariate analyses of logistic regression. Betel quid chewing (OR: 45.98, 95%CI: 10.34-204.49) and cigarette smoking (OR:6.94, 95%CI: 1.60-30.16) were the independent risk factors for OSCC in Taiwan. In addition, a negative correlation between age and melatonin level was observed in healthy controls (Pearson r = -0.24, p = 0.03). However, the negative correlation was lost in patients with OSCC. Melatonin concentration had no association with the severity of OSCC. CONCLUSION: Overall, our study provides evidence that serum melatonin levels decreased in OSCC patients in Taiwan and the decreased level is much significant in young populations and suggests that the decreased melatonin was associated with OSCC, especially in young populations. Further studies are warranted to investigate whether melatonin can be a useful non-invasive screening tool for OSCC.
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Chloroquine (CQ) and its derivative, hydroxychloroquine (HCQ), have attracted wide attention for treating coronavirus disease 2019 (COVID-19). However, conflicting outcomes have been found in COVID-19 clinical trials after treatment with CQ or HCQ. To date, it remains uncertain whether CQ and HCQ are beneficial antiviral drugs for combating COVID-19. We performed a systematic review to depict the efficacy of CQ or HCQ for the treatment of COVID-19. The guidelines of PRISMA were used to conduct this systematic review. We searched through articles from PubMed, Web of Science and other sources that were published from 1 January 2020 to 31 October 2020. The search terms included combinations of human COVID-19, CQ, and HCQ. Eleven qualitative articles comprising of four clinical trials and seven observation studies were utilized in our systematic review. The analysis shows that CQ and HCQ do not have efficacy in treatment of patients with severe COVID-19. In addition, CQ and HCQ have caused life-threatening adverse reactions which included cardiac arrest, electrocardiogram modification, and QTc prolongation, particularly during the treatment of patients with severe COVID-19. Our systematic review suggested that CQ and HCQ are not beneficial antiviral drugs for curing patients with severe COVID-19. The treatment effect of CQ and HCQ is not only null but also causes serious side effects, which may cause potential cardiotoxicity in severe COVID-19 patients.
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An ergostane type triterpenoid methylantcinate A (MAA) isolated from the fruiting bodies of Antrodia camphorata inhibited the growth of oral cancer cell lines OEC-M1 and OC-2 in a dose-dependent manner, without cytotoxic to normal oral gingival fibroblast cells. The major mechanism of growth inhibition was apoptosis induction, as shown by flow cytometric analysis of annexin V-FITC and propidium iodide staining, caspase-3 activation and DNA fragmentation. The increased expression of pro-apoptotic Bax, poly-(ADP-ribose) polymerase cleavage, and activated caspase-3 and decreased expression of anti-apoptotic Bcl-2 and Bcl-xL were also observed. These results provide the first evidence that the anti-oral cancer effects of MAA may involve a mechanism through the mitochondrial dependent pathway. Thus, results reported here may offer further impulse to the development of MAA analogues as potential chemotherapeutic targets for oral cancer complications.
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Antineoplásicos/farmacología , Antrodia/química , Apoptosis/efectos de los fármacos , Neoplasias de la Boca/tratamiento farmacológico , Triterpenos/farmacología , Proteína X Asociada a bcl-2/metabolismo , Antineoplásicos/aislamiento & purificación , Caspasa 3/metabolismo , Línea Celular , Línea Celular Tumoral , Fibroblastos/efectos de los fármacos , Cuerpos Fructíferos de los Hongos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Triterpenos/aislamiento & purificación , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays an important role in the development of HCC. The difficulty in detecting HCC at the early stages is one of the main reasons that the death rate approximates the incidence rate. The regulators controlling the downstream liver protein expression from HBV infection are unclear. Mass spectrometric techniques and customized programs were used to identify differentially expressed proteins which may be involved in the development of liver fibrosis and HCC progression in hepatitis B virus X protein transgenic mice (HBx mice). FSTL1, CTSB, and TGF-ß enhanced the signaling pathway proteins during the pathogenesis of HBx. Missing proteins can be essential in cell growth, differentiation, apoptosis, migration, metastasis or angiogenesis. We found that LHX2, BMP-5 and GDF11 had complex interactions with other missing proteins and BMP-5 had both tumor suppressing and tumorigenic roles. BMP-5 may be involved in fibrosis and tumorigenic processes in the liver. These results provide us an understanding of the mechanism of HBx-induced disorders, and may serve as molecular targets for liver treatment.
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This study investigated the mechanism by which the transcription factor Sp1 is degraded in prostate cancer cells. We recently developed a thiazolidinedione derivative, (Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexyl)-thiazolidine-2,4-dione (OSU-CG12), that induces Sp1 degradation in a manner paralleling that of glucose starvation. Based on our finding that thiazolidinediones suppress beta-catenin and cyclin D1 by up-regulating the E3 ligase SCF(beta-TrCP), we hypothesized that beta-transducin repeat-containing protein (beta-TrCP) targets Sp1 for proteasomal degradation in response to glucose starvation or OSU-CG12. Here we show that either treatment of LNCaP cells increased specific binding of Sp1 with beta-TrCP. This direct binding was confirmed by in vitro pull-down analysis with bacterially expressed beta-TrCP. Although ectopic expression of beta-TrCP enhanced the ability of OSU-CG12 to facilitate Sp1 degradation, suppression of endogenous beta-TrCP function by a dominant-negative mutant or small interfering RNA-mediated knockdown blocked OSU-CG12-facilitated Sp1 ubiquitination and/or degradation. Sp1 contains a C-terminal conventional DSG destruction box ((727)DSGAGS(732)) that mediates beta-TrCP recognition and encompasses a glycogen synthase kinase 3beta (GSK3beta) phosphorylation motif (SXXXS). Pharmacological and molecular genetic approaches and mutational analyses indicate that extracellular signal-regulated kinase-mediated phosphorylation of Thr739 and GSK3beta-mediated phosphorylation of Ser728 and Ser732 were critical for Sp1 degradation. The ability of OSU-CG12 to mimic glucose starvation to activate beta-TrCP-mediated Sp1 degradation has translational potential to foster novel strategies for cancer therapy.
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Glucosa/deficiencia , Factor de Transcripción Sp1/metabolismo , Tiazolidinedionas/farmacología , Proteínas con Repetición de beta-Transducina/biosíntesis , Línea Celular Tumoral , Femenino , Glucógeno Sintasa Quinasa 3/fisiología , Glucógeno Sintasa Quinasa 3 beta , Humanos , MAP Quinasa Quinasa 1/fisiología , Masculino , Fosforilación , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Regulación hacia ArribaRESUMEN
Glycine N-methyltransferase is a tumor suppressor gene for hepatocellular carcinoma, which can activate DNA methylation by inducing the S-adenosylmethionine to S-adenosylhomocystine. Previous studies have indicated that the expression of Glycine N-methyltransferase is inhibited in hepatocellular carcinoma. To confirm and identify missing proteins, the pathologic analysis of the tumor-bearing mice will provide critical histologic information. Such a mouse model is applied as a screening tool for hepatocellular carcinoma as well as a strategy for missing protein discovery. In this study we designed an analysis platform using the human proteome atlas to compare the possible missing proteins to human whole chromosomes. This will integrate the information from animal studies to establish an optimal technique in the missing protein biomarker discovery.
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The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1ß, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfß1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.
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Factores Quimiotácticos/metabolismo , Retroalimentación Fisiológica , Repitelización , Proteínas S100/metabolismo , Piel/citología , Proteína p53 Supresora de Tumor/metabolismo , Cicatrización de Heridas , Actinas/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Factores Quimiotácticos/genética , Colágeno/metabolismo , Ciclooxigenasa 2/genética , Células Epiteliales/citología , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Humanos , Queratinocitos/citología , Masculino , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas S100/genética , Piel/metabolismo , Transcripción Genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
S100A2 is considered a putative tumor suppressor due to its loss or down-regulation in several cancer types. However, no mechanism has been described for the tumor suppressor role of S100A2. In this study, ectopic expression of S100A2 in the human malignant squamous cell carcinoma cell line KB resulted in a significant inhibition of proliferation, migration, and invasion. Moreover, S100A2 significantly reduced the number of colonies (>or=0.5 mm) formed in semisolid agar and decreased tumor growth and burden in nude mice. cDNA microarray analysis was used to compare mRNA expression profiles of vector- and S100A2-expressing isogenic cells. Among the genes deregulated by S100A2, the expression of cyclooxygenase-2 (COX-2) mRNA was significantly suppressed by S100A2 (2.4-fold). Western blot analysis confirmed that S100A2 reduced the expression of COX-2 protein in stably and transiently transfected KB and RPMI-2650 cells. COX-2 is frequently overexpressed in various types of cancer and plays an important role in tumor progression. Partial restoration of COX-2 expression attenuated the antitumor effect of S100A2 both in vitro and in vivo. Although the interplay between S100A2 and COX-2 remains to be clarified, these findings first showed a potent antitumor role of S100A2 in squamous cell carcinoma partly via reduced expression of COX-2.
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Carcinoma de Células Escamosas/metabolismo , Factores Quimiotácticos/fisiología , Ciclooxigenasa 2/fisiología , Genes Supresores de Tumor , Proteínas S100/fisiología , Animales , Ciclo Celular , División Celular , Movimiento Celular/genética , Proliferación Celular , Factores Quimiotácticos/metabolismo , Ciclooxigenasa 2/metabolismo , Fase G2 , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Invasividad Neoplásica/genética , Células Madre Neoplásicas , ARN Mensajero/metabolismo , Proteínas S100/metabolismo , Transfección , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer. METHODS: Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model. RESULTS: AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo. CONCLUSION: AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pancreáticas/patología , Fenilbutiratos/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Researchers have reported significant effects from Danshen (Salvia miltiorrhiza) in terms of inhibiting tumor cell proliferation and promoting apoptosis in breast cancer, hepatocellular carcinomas, promyelocytic leukemia, and clear cell ovary carcinomas. Here we report our data indicating that Danshen extracts, especially alcohol extract, significantly inhibited the proliferation of the human oral squamous carcinoma (OSCC) cell lines HSC-3 and OC-2. We also observed that Danshen alcohol extract activated the caspase-3 apoptosis executor by impeding members of the inhibitor of apoptosis (IAP) family, but not by regulating the Bcl-2-triggered mitochondrial pathway in OSCC cells. Our data also indicate that the extract exerted promising effects in vivo, with HSC-3 tumor xenograft growth being suppressed by 40% and 69% following treatment with Danshen alcohol extract at 50 and 100 mg/kg, respectively, for 34 days. Combined, our results indicate appreciable anticancer activity and significant potential for Danshen alcohol extract as a natural antioxidant and herbal human oral cancer chemopreventive drug.
RESUMEN
[This corrects the article DOI: 10.1155/2017/5364010.].