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[PMID]:29288363
[Au] Autor:Hamurcu Z; Delibasi N; Geçene S; Sener EF; Dönmez-Altuntas H; Özkul Y; Canatan H; Ozpolat B
[Ad] Endereço:Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
[Ti] Título:Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin ß1/ Src signaling in triple negative breast cancer cells.
[So] Source:J Cancer Res Clin Oncol;144(3):415-430, 2018 Mar.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Autophagy is a catabolic process for degrading dysfunctional proteins and organelles, and closely associated with cancer cell survival under therapeutic, metabolic stress, hypoxia, starvation and lack of growth factors, contributing to resistance to therapies. However, the role of autophagy in breast cancer cells is not well understood. In the present study, we investigated the role of autophagy in highly aggressive and metastatic triple negative breast cancer (TNBC) and non-metastatic breast cancer cells and demonstrated that the knockdown of autophagy-related genes (LC3 and Beclin-1) inhibited autophagy and significantly suppressed cell proliferation, colony formation, migration/invasion and induced apoptosis in MDA-MB-231 and BT-549 TNBC cells. Knockdown of LC3 and Beclin-1 led to inhibition of multiple proto-oncogenic signaling pathways, including cyclin D1, uPAR/integrin-ß1/Src, and PARP1. In conclusion, our study suggests that LC3 and Beclin-1 are required for cell proliferation, survival, migration and invasion, and may contribute to tumor growth and progression of highly aggressive and metastatic TNBC cells and therapeutic targeting of autophagy genes may be a potential therapeutic strategy for TNBC in breast cancer.
[Mh] Termos MeSH primário: Beclina-1/antagonistas & inibidores
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Proteínas Associadas aos Microtúbulos/antagonistas & inibidores
Terapia de Alvo Molecular/métodos
RNA Interferente Pequeno/farmacologia
Neoplasias de Mama Triplo Negativas/patologia
[Mh] Termos MeSH secundário: Autofagia/genética
Beclina-1/genética
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Ciclina D1/antagonistas & inibidores
Ciclina D1/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Integrina beta1/metabolismo
Células MCF-7
Proteínas Associadas aos Microtúbulos/genética
Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
Neoplasias de Mama Triplo Negativas/genética
Quinases da Família src/antagonistas & inibidores
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (CCND1 protein, human); 0 (Integrin beta1); 0 (Microtubule-Associated Proteins); 0 (RNA, Small Interfering); 0 (Receptors, Urokinase Plasminogen Activator); 0 (light chain 3, human); 136601-57-5 (Cyclin D1); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2557-5


  2 / 2762 MEDLINE  
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[PMID]:29172777
[Au] Autor:Liu X; Liu X; Sunchen S; Liu M; Shen C; Wu J; Zhao W; Yu B; Liu J
[Ad] Endereço:a State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , PR China.
[Ti] Título:A novel tumor-activated ALA fusion protein for specific inhibition on the growth and invasion of breast cancer cells MDA-MB-231.
[So] Source:Drug Deliv;24(1):1811-1817, 2017 Nov.
[Is] ISSN:1521-0464
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The aim of this research was to develop a novel ALA fusion protein for target to the malignant cells surface with high uPAR expression and locally release of the scorpion toxin AGAP in an uPA-cleavable manner. It will provide an effective approach for controlled release of the peptide toxins to treat cancerous cells. METHODS: The ALA fusion proteins were expressed in pichia pastoris, and the recombinant proteins were purified by Ni-NTA affinity chromatography. The proteins were added to human breast cancer cells (MDA-MB-231) and human embryonic kidney cells (HEK-293) in order to investigate the characteristic of selective targeting and releasing of scorpion toxin AGAP in cancer cells with high uPAR expression. The inhibitory effect of ALA on MDA-MB-231, MCF7, LO2 and HEK-293 was evaluated by MTT assay. Moreover, the antiproliferation mechanism of ALA was determined by flow cytometric and western blot analysis. RESULTS: The results showed that ALA could target MDA-MB-231 cells and the scorpion toxin AGAP could be released with high efficiency and selectivity. ALA inhibited the growth and invasion of breast cancer cells MDA-MB231. Also, cell apoptosis pathway was found to be associated with the inhibition mechanism of ALA according to the data of flow cytometric and western blot analysis. Therefore, ALA could be a novel antitumor candidate for targeting treatment of malignant cell. CONCLUSIONS: This study successfully demonstrated that fusion of biotoxins with tumor target domain could provide a simple yet effective way to delivery of peptide or protein drugs.
[Mh] Termos MeSH primário: Neoplasias da Mama/tratamento farmacológico
Proliferação Celular/efeitos dos fármacos
Invasividade Neoplásica/patologia
Proteínas Recombinantes de Fusão/farmacologia
Venenos de Escorpião/farmacologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Neoplasias da Mama/metabolismo
Linhagem Celular Tumoral
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células HEK293
Seres Humanos
Células MCF-7
Proteínas de Neoplasias/metabolismo
Peptídeos/farmacologia
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (Peptides); 0 (Receptors, Urokinase Plasminogen Activator); 0 (Recombinant Fusion Proteins); 0 (Scorpion Venoms)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180130
[Lr] Data última revisão:
180130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1080/10717544.2017.1406560


  3 / 2762 MEDLINE  
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[PMID]:27777073
[Au] Autor:Hau AM; Leivo MZ; Gilder AS; Hu JJ; Gonias SL; Hansel DE
[Ad] Endereço:Departments of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
[Ti] Título:mTORC2 activation is regulated by the urokinase receptor (uPAR) in bladder cancer.
[So] Source:Cell Signal;29:96-106, 2017 01.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mammalian target of rapamycin complex 2 (mTORC2) has been identified as a major regulator of bladder cancer cell migration and invasion. Upstream pathways that mediate mTORC2 activation remain poorly defined. Urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein and known activator of cell-signaling. We identified increased uPAR expression in 94% of invasive human bladder cancers and in 54-71% of non-invasive bladder cancers, depending on grade. Normal urothelium was uPAR-immunonegative. Analysis of publicly available datasets identified uPAR gene amplification or mRNA upregulation in a subset of bladder cancer patients with reduced overall survival. Using biochemical approaches, we showed that uPAR activates mTORC2 in bladder cancer cells. Highly invasive bladder cancer cell lines, including T24, J82 and UM-UC-3 cells, showed increased uPAR mRNA expression and protein levels compared with the less aggressive cell lines, UROtsa and RT4. uPAR gene-silencing significantly reduced phosphorylation of Serine-473 in Akt, an mTORC2 target. uPAR gene-silencing also reduced bladder cancer cell migration and Matrigel invasion. S473 phosphorylation was observed by immunohistochemistry in human bladder cancers only when the tumors expressed high levels of uPAR. S473 phosphorylation was not controlled by uPAR in bladder cancer cell lines that are PTEN-negative; however, this result probably did not reflect altered mTORC2 regulation. Instead, PTEN deficiency de-repressed alternative kinases that phosphorylate S473. Our results suggest that uPAR and mTORC2 are components of a single cell-signaling pathway. Targeting uPAR or mTORC2 may be beneficial in patients with bladder cancer.
[Mh] Termos MeSH primário: Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Neoplasias da Bexiga Urinária/metabolismo
Neoplasias da Bexiga Urinária/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Linhagem Celular Tumoral
Movimento Celular
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Gradação de Tumores
Invasividade Neoplásica
Fosforilação
Fosfosserina/metabolismo
Prognóstico
Proteínas Proto-Oncogênicas c-akt/metabolismo
Regulação para Cima
Neoplasias da Bexiga Urinária/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Urokinase Plasminogen Activator); 17885-08-4 (Phosphoserine); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180124
[Lr] Data última revisão:
180124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:29202399
[Au] Autor:Yousif AM; Ingangi V; Merlino F; Brancaccio D; Minopoli M; Bellavita R; Novellino E; Carriero MV; Carotenuto A; Grieco P
[Ad] Endereço:Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy; Department of Chemistry, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, United States.
[Ti] Título:Urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type 1-triggered cell migration.
[So] Source:Eur J Med Chem;143:348-360, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration. We and others have previously documented that the uPAR(84-95) sequence, interacts with the formyl peptide receptors (FPR)s, henceforth inducing cell migration of several cell lines, including leukocytes, and the synthetic shorter peptide (Ser -Arg-Ser-Arg-Tyr , SRSRY) retains chemotactic activity in vitro and in vivo. Recently, we have developed the head-to-tail cyclic analog [SRSRY], a new potent and stable inhibitor of monocyte trafficking. This prompted us to develop novel cyclic and linear analogs of [SRSRY] with the aim to broaden the knowledge about structure-activity relationships of peptide [SRSRY]. Herein we report their synthesis, effects on cell migration, conformational and docking analyses which served to envisage a new pharmacophore model for inhibitors of FPR1-triggered cell migration.
[Mh] Termos MeSH primário: Peptídeos/farmacologia
Receptores de Formil Peptídeo/antagonistas & inibidores
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Peptídeos/síntese química
Peptídeos/química
Ratos
Receptores de Ativador de Plasminogênio Tipo Uroquinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FPR1 protein, human); 0 (Peptides); 0 (Receptors, Formyl Peptide); 0 (Receptors, Urokinase Plasminogen Activator)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:28931568
[Au] Autor:Diaz A; Merino P; Manrique LG; Ospina JP; Cheng L; Wu F; Jeanneret V; Yepes M
[Ad] Endereço:Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
[Ti] Título:A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain.
[So] Source:J Neurosci;37(43):10310-10322, 2017 Oct 25.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that uPA and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that uPA binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either uPA (uPA ) or uPAR (uPAR ) or with a four-amino acid substitution into the growth factor domain of uPA that abrogates its binding to uPAR ( ) to investigate the mechanism whereby uPA promotes neurorepair in the ischemic brain. We found that neurons release uPA and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal uPA to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that uPA/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal uPA promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that uPA/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain. To date, there is no therapeutic strategy to promote synaptic recovery in the injured brain. Here, we show that neurons release urokinase-type plasminogen activator (uPA) and astrocytes recruit the uPA receptor (uPAR) to their plasma membrane during the recovery phase from a hypoxic injury. We found that binding of neuronal uPA to astrocytic uPAR promotes astrocytic activation and that astrocytes activated by uPA-uPAR binding promote synaptic recovery in neurons that have suffered a hypoxic injury by a mechanism that does not require plasmin generation, but instead is mediated by ERK1/2-regulated STAT3 phosphorylation, astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). Our work unveils a new biological function for uPA-uPAR as mediator of a neuron-astrocyte cross talk that promotes synaptic recovery in the ischemic brain.
[Mh] Termos MeSH primário: Astrócitos/metabolismo
Isquemia Encefálica/metabolismo
Receptor Cross-Talk/fisiologia
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Sinapses/fisiologia
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Astrócitos/patologia
Isquemia Encefálica/patologia
Células Cultivadas
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Neurônios/metabolismo
Neurônios/patologia
Recuperação de Função Fisiológica/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Urokinase Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1630-17.2017


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[PMID]:28869084
[Au] Autor:Ding F; Chen S; Zhang W; Tu Y; Sun Y
[Ad] Endereço:Key Laboratory of Pesticides and Chemical Biology, Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, College of Chemistry, Central China Normal University, Wuhan 430079, China.
[Ti] Título:UPAR targeted molecular imaging of cancers with small molecule-based probes.
[So] Source:Bioorg Med Chem;25(20):5179-5184, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Molecular imaging can allow the non-invasive characterization and measurement of biological and biochemical processes at the molecular and cellular levels in living subjects. The imaging of specific molecular targets that are associated with cancers could allow for the earlier diagnosis and better treatment of diseases. Small molecule-based probes play prominent roles in biomedical research and have high clinical translation ability. Here, with an emphasis on small molecule-based probes, we review some recent developments in biomarkers, imaging techniques and multimodal imaging in molecular imaging and highlight the successful applications for molecular imaging of cancers.
[Mh] Termos MeSH primário: Corantes Fluorescentes/química
Imagem Molecular
Sondas Moleculares/química
Neoplasias/diagnóstico por imagem
Receptores de Ativador de Plasminogênio Tipo Uroquinase/análise
Bibliotecas de Moléculas Pequenas/química
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Molecular Probes); 0 (Receptors, Urokinase Plasminogen Activator); 0 (Small Molecule Libraries)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28818858
[Au] Autor:Hohensinner PJ; Baumgartner J; Kral-Pointner JB; Uhrin P; Ebenbauer B; Thaler B; Doberer K; Stojkovic S; Demyanets S; Fischer MB; Huber K; Schabbauer G; Speidl WS; Wojta J
[Ad] Endereço:From the Department of Internal Medicine II, Division of Cardiology (P.J.H., J.B., B.E., B.T., K.D., S.S., S.D., W.S.S., J.W.), Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research (J.B.K.-P., P.U., G.S.), Department of Laboratory Medicine (S.D.), Clinic for
[Ti] Título:PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent.
[So] Source:Arterioscler Thromb Vasc Biol;37(10):1913-1922, 2017 Oct.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages. APPROACH AND RESULTS: We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1 bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss. CONCLUSIONS: We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1.
[Mh] Termos MeSH primário: Macrófagos/metabolismo
Inibidor 1 de Ativador de Plasminogênio/metabolismo
Proteólise
[Mh] Termos MeSH secundário: Fibrose
Seres Humanos
Pulmão/enzimologia
Pulmão/patologia
Metaloproteinase 14 da Matriz/metabolismo
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plasminogen Activator Inhibitor 1); 0 (Receptors, Urokinase Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); EC 3.4.24.80 (MMP14 protein, human); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309383


  8 / 2762 MEDLINE  
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[PMID]:28666875
[Au] Autor:Lulli M; Cammalleri M; Granucci I; Witort E; Bono S; Di Gesualdo F; Lupia A; Loffredo R; Casini G; Dal Monte M; Capaccioli S
[Ad] Endereço:Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy. Electronic address: matteo.lulli@unifi.it.
[Ti] Título:In vitro and in vivo inhibition of proangiogenic retinal phenotype by an antisense oligonucleotide downregulating uPAR expression.
[So] Source:Biochem Biophys Res Commun;490(3):977-983, 2017 Aug 26.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neoangiogenesis is the main pathogenic event involved in a variety of retinal diseases. It has been recently demonstrated that inhibiting the urokinase-type plasminogen activator receptor (uPAR) results in reduced angiogenesis in a mouse model of oxygen-induced retinopathy (OIR), establishing uPAR as a therapeutic target in proliferative retinopathies. Here, we evaluated in cultured human retinal endothelial cells (HRECs) and in OIR mice the potential of a specific antisense oligodeoxyribonucleotide (ASO) in blocking the synthesis of uPAR and in providing antiangiogenic effects. uPAR expression in HRECs was inhibited by lipofection with the phosphorotioated 5'-CGGCGGGTGACCCATGTG-3' ASO-uPAR, complementary to the initial translation site of uPAR mRNA. Inhibition of uPAR expression via ASO-uPAR was evaluated in HRECs by analyzing VEGF-induced tube formation and migration. In addition, the well-established and reproducible murine OIR model was used to induce retinal neovascularization in vivo. OIR mice were injected intraperitoneally with ASO-uPAR and retinopathy was evaluated considering the extent of the avascular area in the central retina and neovascular tuft formation. The ASO-uPAR specifically decreased uPAR mRNA and protein levels in HRECs and mitigated VEGF-induced tube formation and cell migration. Noteworthy, in OIR mice ASO-uPAR administration reduced both the avascular area and the formation of neovascular tufts. In conclusion, although the extrapolation of these experimental findings to the clinic is not straightforward, ASO-uPAR may be considered a potential therapeutic tool for treatment of proliferative retinal diseases.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/uso terapêutico
Oligodesoxirribonucleotídeos Antissenso/uso terapêutico
Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética
Retina/patologia
Neovascularização Retiniana/genética
Neovascularização Retiniana/terapia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/genética
Animais
Linhagem Celular
Movimento Celular/efeitos dos fármacos
Modelos Animais de Doenças
Terapia Genética
Seres Humanos
Camundongos
Oligodesoxirribonucleotídeos Antissenso/genética
RNA Mensageiro/genética
Receptores de Ativador de Plasminogênio Tipo Uroquinase/análise
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Retina/citologia
Retina/metabolismo
Neovascularização Retiniana/metabolismo
Neovascularização Retiniana/patologia
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Oligodeoxyribonucleotides, Antisense); 0 (RNA, Messenger); 0 (Receptors, Urokinase Plasminogen Activator); 0 (Vascular Endothelial Growth Factor A)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


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[PMID]:28650456
[Au] Autor:Hayek SS; Koh KH; Grams ME; Wei C; Ko YA; Li J; Samelko B; Lee H; Dande RR; Lee HW; Hahm E; Peev V; Tracy M; Tardi NJ; Gupta V; Altintas MM; Garborcauskas G; Stojanovic N; Winkler CA; Lipkowitz MS; Tin A; Inker LA; Levey AS; Zeier M; Freedman BI; Kopp JB; Skorecki K; Coresh J; Quyyumi AA; Sever S; Reiser J
[Ad] Endereço:Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
[Ti] Título:A tripartite complex of suPAR, APOL1 risk variants and α ß integrin on podocytes mediates chronic kidney disease.
[So] Source:Nat Med;23(8):945-953, 2017 Aug.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and α ß integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments α ß integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on α ß integrin activation is a mechanism for CKD.
[Mh] Termos MeSH primário: Apolipoproteínas/genética
Integrina alfaVbeta3/metabolismo
Lipoproteínas HDL/genética
Podócitos/metabolismo
Proteinúria/genética
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Insuficiência Renal Crônica/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Afroamericanos
Idoso
Alelos
Animais
Apolipoproteína L1
Apolipoproteínas/metabolismo
Estudos de Coortes
Feminino
Predisposição Genética para Doença
Genótipo
Seres Humanos
Lipoproteínas HDL/metabolismo
Masculino
Camundongos
Meia-Idade
Proteinúria/metabolismo
Insuficiência Renal Crônica/metabolismo
Ressonância de Plasmônio de Superfície
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APOL1 protein, human); 0 (Apolipoprotein L1); 0 (Apolipoproteins); 0 (Integrin alphaVbeta3); 0 (Lipoproteins, HDL); 0 (Receptors, Urokinase Plasminogen Activator)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4362


  10 / 2762 MEDLINE  
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[PMID]:28577299
[Au] Autor:Laurenzana A; Chillà A; Luciani C; Peppicelli S; Biagioni A; Bianchini F; Tenedini E; Torre E; Mocali A; Calorini L; Margheri F; Fibbi G; Del Rosso M
[Ad] Endereço:Department of Experimental and Clinical Biomedical Sciences, Section of Experimental Pathology and Oncology, University of Florence, Florence, 50134, Italy.
[Ti] Título:uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells.
[So] Source:Int J Cancer;141(6):1190-1200, 2017 Sep 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5ß1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL-TKRs axis) for the therapy of melanoma.
[Mh] Termos MeSH primário: Melanoma/metabolismo
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Regulação para Baixo
Feminino
Glicólise
Células HEK293
Xenoenxertos
Seres Humanos
Melanoma/patologia
Camundongos
Camundongos Nus
Camundongos SCID
Invasividade Neoplásica
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PLAUR protein, human); 0 (Receptors, Urokinase Plasminogen Activator); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30817



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