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Pesquisa : D08.811.913.696.620.682.725.400.185 [Categoria DeCS]
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[PMID]:29028222
[Au] Autor:Choi HJ; Joo HS; Won HY; Min KW; Kim HY; Son T; Oh YH; Lee JY; Kong G
[Ad] Endereço:Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University,
[Ti] Título:Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.
[So] Source:J Natl Cancer Inst;110(4), 2018 Apr 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Carcinoma Ductal de Mama/metabolismo
Resistência a Medicamentos Antineoplásicos
Proteínas de Neoplasias/fisiologia
Receptores Estrogênicos/metabolismo
Proteína 2 de Ligação ao Retinoblastoma/fisiologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Análise de Variância
Animais
Antineoplásicos Hormonais/uso terapêutico
Neoplasias da Mama/química
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/química
Carcinoma Ductal de Mama/tratamento farmacológico
Carcinoma Ductal de Mama/patologia
Proteínas de Transporte/metabolismo
Estudos de Coortes
Colorimetria
Intervalo Livre de Doença
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Xenoenxertos
Seres Humanos
Estimativa de Kaplan-Meier
Células MCF-7
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Proteínas de Neoplasias/metabolismo
Células-Tronco Neoplásicas
Proteínas Nucleares/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/metabolismo
Receptor ErbB-2/metabolismo
Receptor IGF Tipo 1/metabolismo
Proteína 2 de Ligação ao Retinoblastoma/metabolismo
Tamoxifeno/uso terapêutico
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents, Hormonal); 0 (Carrier Proteins); 0 (IGFBP5-interacting protein, human); 0 (Neoplasm Proteins); 0 (Nuclear Proteins); 0 (Receptors, Estrogen); 0 (nuclear receptor interacting protein 1); 094ZI81Y45 (Tamoxifen); EC 1.14.11.27 (Retinoblastoma-Binding Protein 2); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171014
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx207


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[PMID]:28454723
[Au] Autor:Ma Y; Fu S; Lu L; Wang X
[Ad] Endereço:School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China.
[Ti] Título:Role of androgen receptor on cyclic mechanical stretch-regulated proliferation of C2C12 myoblasts and its upstream signals: IGF-1-mediated PI3K/Akt and MAPKs pathways.
[So] Source:Mol Cell Endocrinol;450:83-93, 2017 Jul 15.
[Is] ISSN:1872-8057
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:OBJECTS: To detect the effects of androgen receptor (AR) on cyclic mechanical stretch-modulated proliferation of C2C12 myoblasts and its pathways: roles of IGF-1, PI3K and MAPK. METHODS: C2C12 were randomly divided into five groups: un-stretched control, six or 8 h of fifteen percent stretch, and six or 8 h of twenty percent stretch. Cyclic mechanical stretch of C2C12 were completed using a computer-controlled FlexCell Strain Unit. Cell proliferation and IGF-1 concentration in medium were detected by CCK8 and ELISA, respectively. Expressions of AR and IGF-1R, and expressions and activities of PI3K, p38 and ERK1/2 in stretched C2C12 cells were determined by Western blot. RESULTS: â‘ The proliferation of C2C12 cells, IGF-1 concentration in medium, expressions of AR and IGF-1R, and activities of PI3K, p38 and ERK1/2 were increased by 6 h of fifteen percent stretch, while decreased by twenty percent stretch for six or 8 h â‘¡The fifteen percent stretch-increased proliferation of C2C12 cells was reversed by AR inhibitor, Flutamide. â‘¢The increases of AR expression, activities of PI3K, p38 and ERK1/2 resulted from fifteen percent stretch were attenuated by IGF-1 neutralizing antibody, while twenty percent stretch-induced decreases of the above indicators were enhanced by recombinant IGF-1. â‘£Specific inhibitors of p38, ERK1/2 and PI3K all decreased the expression of AR in fifteen percent and twenty percent of stretched C2C12 cells. CONCLUSIONS: Cyclic mechanical stretch modulated the proliferation of C2C12 cells, which may be attributed to the alterations of AR via IGF-1-PI3K/Akt and IGF-1-MAPK (p38, ERK1/2) pathways in C2C12 cells.
[Mh] Termos MeSH primário: Fator de Crescimento Insulin-Like I/metabolismo
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Mioblastos/citologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptores Androgênicos/metabolismo
Estresse Mecânico
[Mh] Termos MeSH secundário: Animais
Anticorpos Neutralizantes/farmacologia
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Camundongos
Mioblastos/efeitos dos fármacos
Mioblastos/enzimologia
Mioblastos/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Receptor IGF Tipo 1/metabolismo
Proteínas Recombinantes/farmacologia
Transdução de Sinais/efeitos dos fármacos
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (Protein Kinase Inhibitors); 0 (Receptors, Androgen); 0 (Recombinant Proteins); 67763-96-6 (Insulin-Like Growth Factor I); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29253837
[Au] Autor:Christopoulos PF; Corthay A; Koutsilieris M
[Ad] Endereço:Department of Experimental Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece; Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Medical Biology, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway. Electronic address: christopoulos.panagiotis@rr-research.no.
[Ti] Título:Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics.
[So] Source:Cancer Treat Rev;63:79-95, 2018 Feb.
[Is] ISSN:1532-1967
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty-five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro-environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Receptor IGF Tipo 1/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 67763-96-6 (Insulin-Like Growth Factor I); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE


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[PMID]:29272313
[Au] Autor:Piñeiro-Hermida S; Alfaro-Arnedo E; Gregory JA; Torrens R; Ruíz-Martínez C; Adner M; López IP; Pichel JG
[Ad] Endereço:Lung Cancer and Respiratory Diseases Unit, Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain.
[Ti] Título:Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma.
[So] Source:PLoS One;12(12):e0190159, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology. Additionally, Igf1r-deficiency was therapeutically induced in mice to evaluate the resolution of HDM-induced inflammation. Acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammation, airway remodeling and associated molecular indicators. Preventively-induced Igf1r-deficiency showed reduced neutrophil and eosinophil numbers in BALF and bone marrow, a significant reduction of airway remodeling and decreased levels of related markers. In addition, therapeutic targeting of Igf1r promoted the resolution of HDM-induced-inflammation. Our results demonstrate for the first time that Igf1r is important in acute asthma pathobiology and resolution of HDM-induced inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment and prevention of asthma.
[Mh] Termos MeSH primário: Asma/terapia
Modelos Animais de Doenças
Marcação de Genes
Inflamação/terapia
Receptor IGF Tipo 1/genética
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Células da Medula Óssea
Líquido da Lavagem Broncoalveolar
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190159


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[PMID]:28977588
[Au] Autor:Mosa R; Huang L; Wu Y; Fung C; Mallawakankanamalage O; LeRoith D; Chen C
[Ad] Endereço:School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, Queensland 4072, Australia.
[Ti] Título:Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice.
[So] Source:Endocrinology;158(10):3174-3187, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of hexarelin (200 µg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with hexarelin treatment. Interestingly, although food intake of hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of hexarelin in treatment of lipid disorders associated with the metabolic syndrome.
[Mh] Termos MeSH primário: Dislipidemias/tratamento farmacológico
Hormônio do Crescimento/secreção
Resistência à Insulina
Oligopeptídeos/administração & dosagem
[Mh] Termos MeSH secundário: Adipócitos/efeitos dos fármacos
Tecido Adiposo/metabolismo
Animais
Glicemia/análise
Composição Corporal/efeitos dos fármacos
Dislipidemias/complicações
Intolerância à Glucose/tratamento farmacológico
Hormônio do Crescimento/efeitos dos fármacos
Insulina/sangue
Metabolismo dos Lipídeos/efeitos dos fármacos
Lipídeos/sangue
Fígado/química
Masculino
Síndrome Metabólica/complicações
Camundongos
Camundongos Mutantes
Músculo Esquelético/metabolismo
Mutação
Obesidade
Receptor IGF Tipo 1/genética
Triglicerídeos/análise
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); 0 (Lipids); 0 (Oligopeptides); 0 (Triglycerides); 09QF37C617 (hexarelin); 9002-72-6 (Growth Hormone); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00168


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[PMID]:28972999
[Au] Autor:Mohammed RH; Anderton H; Brameld JM; Sweetman D
[Ad] Endereço:School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom.
[Ti] Título:Effects of insulin like growth factors on early embryonic chick limb myogenesis.
[So] Source:PLoS One;12(10):e0185775, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Limb muscles derive from pax3 expressing precursor cells that migrate from the hypaxial somite into the developing limb bud. Once there they begin to differentiate and express muscle determination genes such as MyoD. This process is regulated by a combination of inductive or inhibitory signals including Fgf18, retinoic acid, HGF, Notch and IGFs. IGFs are well known to affect late stages of muscle development and to promote both proliferation and differentiation. We examined their roles in early stage limb bud myogenesis using chicken embryos as an experimental model. Grafting beads soaked in purified recombinant IGF-I, IGF-II or small molecule inhibitors of specific signaling pathways into developing chick embryo limbs showed that both IGF-I and IGF-II induce expression of the early stage myogenic markers pax3 and MyoD as well as myogenin. Their effects on pax3 and MyoD expression were blocked by inhibitors of both the IGF type I receptor (picropodophyllotoxin, PPP) and MEK (U0126). The PI3K inhibitor LY294002 blocked IGF-II, but not IGF-I, induction of pax3 mRNA as well as the IGF-I, but not IGF-II, induction of MyoD mRNA. In addition SU5402, an FGFR/ VEGFR inhibitor, blocked the induction of MyoD by both IGFs but had no effect on pax3 induction, suggesting a role for FGF or VEGF signaling in their induction of MyoD. This was confirmed by in situ hybridization showing that FGF18, a known regulator of MyoD in limb myoblasts, was induced by IGF-I. In addition to their well-known effects on later stages of myogenesis via their induction of myogenin expression, both IGF-I and IGF-II induced pax3 and MyoD expression in developing chick embryos, indicating that they also regulate early stages of myogenesis. The data suggests that the IGFs may have slightly different effects on IGF1R signal transduction via PI3K and that their stimulatory effects on MyoD expression may be indirect, possibly via induction of FGF18 expression.
[Mh] Termos MeSH primário: Embrião de Galinha/efeitos dos fármacos
Membro Posterior/efeitos dos fármacos
Fator de Crescimento Insulin-Like II/farmacologia
Fator de Crescimento Insulin-Like I/farmacologia
Desenvolvimento Muscular/efeitos dos fármacos
Músculo Esquelético/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Butadienos/farmacologia
Embrião de Galinha/metabolismo
Cromonas/farmacologia
Inibidores Enzimáticos/farmacologia
Fatores de Crescimento de Fibroblastos/genética
Fatores de Crescimento de Fibroblastos/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Membro Posterior/metabolismo
Morfolinas/farmacologia
Desenvolvimento Muscular/fisiologia
Músculo Esquelético/metabolismo
Proteína MyoD/genética
Proteína MyoD/metabolismo
Miogenina/genética
Miogenina/metabolismo
Nitrilos/farmacologia
Fator de Transcrição PAX3/genética
Fator de Transcrição PAX3/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Podofilotoxina/análogos & derivados
Podofilotoxina/farmacologia
Pirróis/farmacologia
Receptor IGF Tipo 1/antagonistas & inibidores
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Butadienes); 0 (Chromones); 0 (Enzyme Inhibitors); 0 (Morpholines); 0 (MyoD Protein); 0 (Myogenin); 0 (Nitriles); 0 (PAX3 Transcription Factor); 0 (Pyrroles); 0 (SU 5402); 0 (U 0126); 0 (fibroblast growth factor 18); 0F35AOI227 (picropodophyllin); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one); 62031-54-3 (Fibroblast Growth Factors); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185775


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[PMID]:28946136
[Au] Autor:Zhao J; Shi X; Wang T; Ying C; He S; Chen Y
[Ad] Endereço:Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, China.
[Ti] Título:The Prognostic and Clinicopathological Significance of IGF-1R in NSCLC: a Meta-Analysis.
[So] Source:Cell Physiol Biochem;43(2):697-704, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Accumulating studies have reported that IGF-1R (Insulin-like growth factor-1 receptor) is aberrantly expressed in NSCLC (non-small cell lung cancer), but the role of IGF-1R in NSCLC remains controversial. The present paper assessed the precise role of IGF-1R in NSCLC. METHODS: We comprehensively searched PubMed, EMBASE, and Web of Science in March 2017. Combined HRs and ORs were used to evaluate the prognostic and clinicopathological significance of IGF-1R in NSCLC respectively. RESULTS: A total of 10 eligible studies including 8 on overall survival, and 10 on clinicopathological features were identified from the databases. The results showed that high expression of IGF-1R was associated with shorter OS (overall survival) of NSCLC patients (pooled HR 1.17,95 % CI 1.00-1.36). In addition, we found that IGF-1R was related to smoking status (OR=1.82, 95 % CI=1.35-2.44) and IGF-1R tended to be highly expressed in SCC (squamous cell carcinoma) (OR=3.40 95 % CI: 1.95-5.95). CONCLUSIONS: In summary, this meta-analysis revealed that high expression of IGF-1R was associated with poor prognosis in NSCLC.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/diagnóstico
Neoplasias Pulmonares/diagnóstico
Pulmão/patologia
Receptor IGF Tipo 1/análise
[Mh] Termos MeSH secundário: Biomarcadores Tumorais/análise
Carcinoma Pulmonar de Células não Pequenas/patologia
Seres Humanos
Neoplasias Pulmonares/patologia
Prognóstico
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1159/000480655


  8 / 5704 MEDLINE  
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[PMID]:28938449
[Au] Autor:Krieger CC; Perry JD; Morgan SJ; Kahaly GJ; Gershengorn MC
[Ad] Endereço:Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
[Ti] Título:TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types.
[So] Source:Endocrinology;158(10):3676-3683, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We previously showed that thyrotropin (TSH)/insulinlike growth factor (IGF)-1 receptor cross-talk appears to be involved in Graves' orbitopathy (GO) pathogenesis and upregulation of thyroid-specific genes in human thyrocytes. In orbital fibroblasts from GO patients, coadministration of TSH and IGF-1 induces synergistic increases in hyaluronan secretion. In human thyrocytes, TSH plus IGF-1 synergistically increased expression of the sodium-iodide symporter that appeared to involve ERK1/2 activation. However, the details of ERK1/2 activation were not known, nor was whether ERK1/2 was involved in this synergism in other cell types. Using primary cultures of GO fibroblasts (GOFs) and human thyrocytes, as well as human embryonic kidney (HEK) 293 cells overexpressing TSH receptors (HEK-TSHRs), we show that simultaneous activation of TSHRs and IGF-1 receptors (IGF-1Rs) causes rapid, synergistic phosphorylation/activation of ERK1 and ERK2 in all three cell types. This effect is partially inhibited by pertussis toxin, an inhibitor of TSHR coupling to Gi/Go proteins. In support of a role for Gi/Go proteins in ERK1/2 phosphorylation, we found that knockdown of Gi(1-3) and Go in HEK-TSHRs inhibited ERK1/2 phosphorylation stimulated by TSH and TSH plus IGF-1. These data demonstrate that the synergistic effects of TSH plus IGF-1 occur early in the TSHR signaling cascade and further support the idea that TSHR/IGF-1R cross-talk is an important mechanism for regulation of human GOFs and thyrocytes.
[Mh] Termos MeSH primário: Fibroblastos/efeitos dos fármacos
Fator de Crescimento Insulin-Like I/farmacologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Receptor Cross-Talk
Receptor IGF Tipo 1/metabolismo
Receptores da Tireotropina/metabolismo
Tireotropina/farmacologia
[Mh] Termos MeSH secundário: Fibroblastos/metabolismo
Oftalmopatia de Graves
Células HEK293
Seres Humanos
Ácido Hialurônico/secreção
Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Fosforilação/efeitos dos fármacos
Simportadores/efeitos dos fármacos
Simportadores/metabolismo
Células Epiteliais da Tireóide/efeitos dos fármacos
Células Epiteliais da Tireóide/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Thyrotropin); 0 (Symporters); 0 (sodium-iodide symporter); 67763-96-6 (Insulin-Like Growth Factor I); 9002-71-5 (Thyrotropin); 9004-61-9 (Hyaluronic Acid); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00528


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[PMID]:28881863
[Au] Autor:François JC; Aïd S; Chaker Z; Lacube P; Xu J; Fayad R; Côté F; Even P; Holzenberger M
[Ad] Endereço:INSERM Research Center Unité 938, 75012 Paris, France.
[Ti] Título:Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses.
[So] Source:Endocrinology;158(7):2269-2283, 2017 Jul 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age-related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer.
[Mh] Termos MeSH primário: Metabolismo Energético/genética
Hormônio do Crescimento/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Receptor IGF Tipo 1/genética
Magreza/genética
[Mh] Termos MeSH secundário: Animais
Composição Corporal/efeitos dos fármacos
Composição Corporal/genética
Metabolismo Energético/efeitos dos fármacos
Feminino
Deleção de Genes
Hormônio do Crescimento Humano/análogos & derivados
Hormônio do Crescimento Humano/farmacologia
Resistência à Insulina/genética
Fator de Crescimento Insulin-Like I/antagonistas & inibidores
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Receptor IGF Tipo 1/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
Magreza/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
12629-01-5 (Human Growth Hormone); 67763-96-6 (Insulin-Like Growth Factor I); 9002-72-6 (Growth Hormone); EC 2.7.10.1 (Receptor, IGF Type 1); N824AOU5XV (pegvisomant)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00261


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[PMID]:28873464
[Au] Autor:Cedano Prieto DM; Cheng Y; Chang CC; Yu J; Takada YK; Takada Y
[Ad] Endereço:Department of Dermatology, Biochemistry and Molecular Medicine, UC Davis School of Medicine, Research III Suite, 4645 Second Avenue, Sacramento, CA, United States of America.
[Ti] Título:Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling.
[So] Source:PLoS One;12(9):e0184285, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins ανß3 and α6ß4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins ανß3 and α6ß4, and induced proliferation of CHO cells (IGF1R+) that express ανß3 or α6ß4 (ß3- or α6ß4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling.
[Mh] Termos MeSH primário: Fator de Crescimento Insulin-Like II/química
Fator de Crescimento Insulin-Like II/metabolismo
Integrina alfa6beta4/metabolismo
Integrina alfaVbeta3/metabolismo
Receptor IGF Tipo 1/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células CHO
Linhagem Celular Tumoral
Proliferação Celular
Cricetinae
Cricetulus
Seres Humanos
Proteínas Mutantes
Ligação Proteica
Domínios Proteicos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha6beta4); 0 (Integrin alphaVbeta3); 0 (Mutant Proteins); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184285



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