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1.
Expert Opin Investig Drugs ; 28(12): 1101-1112, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31731883

RESUMO

Introduction: The insulin-like growth factors (IGFs) are a family of secreted peptide hormones with important roles in different cellular and organism functions. The biological activities of the IGFs are mediated by the IGF1 receptor (IGF1R), a cell surface, tyrosine kinase-containing heterotetramer that is linked to numerous cytoplasmic signaling cascades. The IGF1R displays potent antiapoptotic, pro-survival capacities and plays a key role in malignant transformation. Research has identified the IGF1R as a candidate therapeutic target in cancer.Areas covered: We offer a synopsis of ongoing efforts to target the IGF axis for therapeutic purposes. Our review includes a digest of early experimental work that led to the identification of IGF1R as a candidate therapeutic target in oncology.Expert opinion: Targeting of the IGF axis has yielded disappointing results in phase III trials, but it is important to learn from this to improve future trials in a rational manner. The potential of anti-IGF1R antibodies and small molecular weight inhibitors, alone or in combination with chemotherapy or other biological agents, should be investigated further in randomized studies. Moreover, the implementation of predictive biomarkers for patient selection will improve the outcome of future trials. Emerging personalized medicine could have a major impact on IGF1R targeting.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Seleção de Pacientes , Receptor IGF Tipo 1/metabolismo
2.
Nat Commun ; 10(1): 4427, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562314

RESUMO

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.


Assuntos
Diabetes Mellitus/metabolismo , Hiperplasia/metabolismo , Resistência à Insulina/fisiologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animais , Modelos Animais de Doenças , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Homozigoto , Hialuronan Sintases/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Receptor IGF Tipo 1/química , Receptor de Insulina/química , Transdução de Sinais
3.
Environ Toxicol ; 34(12): 1320-1328, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31486215

RESUMO

Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)-induced tumor necrosis factor-alpha (TNF-α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS-challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose-dependent manner, especially in the LPS + CTF 25 (µg/mL) group. LPS treatment-induced apoptosis was determined by transferase-mediated dUTP nick end labeling assay, and by Western blot. LPS-induced apoptotic bodies were decreased following CTF treatment. Expression of TNF-α, FAS-L, FAS, FADD, caspase-8, BID, and t-BID was significantly increased in LPS-treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl-2 and p-Bad, and downregulates Bax, cytochrome-c, caspase-9, caspase-3, and apoptosis-inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin-like growth factor-I (IGF-I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF-I receptor (IGF-IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF-IR pathway to inhibit LPS-induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS-induced apoptotic response through IGF-I pathway.


Assuntos
Apoptose/efeitos dos fármacos , Carthamus tinctorius/química , Extratos Vegetais/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Carthamus tinctorius/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
4.
Artif Cells Nanomed Biotechnol ; 47(1): 3500-3510, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31432697

RESUMO

Salidroside is an active ingredient extracted from Rhodiola rosea that has anti-tumor activities. The current paper attempted to assess the impact of Salidroside on gastric cancer (GC) and explore the potential mechanism. GC cell lines (SNU-216 and MGC803) and gastric epithelial cell line GES-1 were treated with Salidroside. CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were respectively performed to evaluate GC cells phenotype. qRT-PCR and western blot were conducted to reveal the downstream genes and signaling of Salidroside. We found that 800 µM Salidroside was capable of reducing GC cells viability, while has no such impacts on GES-1 cells. Salidroside inhibited GC cells proliferation, migration, invasion and promoted apoptosis, which coupled with the down-regulation of p21, Bcl-2, MMP2, RhoA, p-ROCK1, Vimentin and the up-regulations of CyclinD1, Bax, cleaved caspases. miR-99a was found to be highly expressed in response to Salidroside treatment. Besides, the inhibition of MAPK/ERK and PI3K/AKT signaling induced by Salidroside was attenuated by miR-99a silence and in this process, IGF1R worked as a target of miR-99a. The anti-GC effect of Salidroside was also confirmed in a mouse model of GC. The promoting effect of Salidroside on miR-99a expression was also verified in vivo. Furthermore, Salidroside promoted the cisplatin-sensitivity of SGC7901/DDP cells. In conclusion, this study demonstrated that Salidroside possessed anti-GC effects through regulating miR-99a/IGF1R axis and inhibiting MAPK/ERK and PI3K/AKT pathways.


Assuntos
Antineoplásicos/farmacologia , Glucosídeos/farmacologia , MicroRNAs/genética , Fenóis/farmacologia , Neoplasias Gástricas/patologia , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Mediators Inflamm ; 2019: 5497467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467485

RESUMO

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.


Assuntos
Carcinoma Nasofaríngeo/metabolismo , Receptor IGF Tipo 1/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Humanos , Imidazóis/farmacologia , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Radiação Ionizante
6.
Nat Commun ; 10(1): 3201, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324758

RESUMO

Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1High SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1High SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors.


Assuntos
Biomarcadores Tumorais , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Azepinas/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Fatores de Transcrição de Octâmero/metabolismo , Proteômica , Pirazóis/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Triazinas/farmacologia , Triazóis/farmacologia
7.
Nutrients ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331066

RESUMO

Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson's disease and possibly other oxidative stress-related neurodegenerative disorders.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Paraquat/farmacologia , Doença de Parkinson , Fosfatidilinositol 3-Quinases/metabolismo , Receptor IGF Tipo 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(2): 158-164, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31309753

RESUMO

OBJECTIVE: To investigate the effect of low-frequency pulsed electromagnetic fields (PEMF) on the maturation and mineralization of rat cranial osteoblasts in vitro and its relation to IGF-1R/NO signaling pathway. METHODS: The rat osteoblasts were isolated and cultured in vitro and randomly divided into blank control group, PEMF group, GSK group (IGF-1R blocker) and PEMF+GSK group. The cells were treated with 50 Hz 0.6 mT PEMF for 1.5 h/d. After 3 d of PEMF treatment, the expressions of protein kinase (AKT), inducible nitric oxide synthase (iNOS) and cGMP-dependent protein kinase (PKG) were detected by Western blotting; on 6 d of PEMF treatment alkaline phosphatase (ALP) activity was determined; on 12 d of PEMF treatment the calcification nodule formation was demonstrated by Alizarin red staining. RESULTS: NO level was significantly increased in rat osteoblasts treated with 50 Hz 0.6 mT PEMF for 1.5 h/d. Western blot analysis showed that the expressions of AKT, iNOS and PKG protein in PEMF group were higher than those in the control group (all P<0.01); the ALP activity was increased(P<0.05), and the PEMF group had the largest area of Alizarin red staining (P<0.01). The expressions of AKT, iNOS and PKG protein in GSK group were lower than those in the control group; the ALP activity was decreased (P<0.05), and the GSK group had the least area of Alizarin red staining (P<0.01). The expressions of AKT, iNOS, PKG protein, the ALP activity and the area of Alizarin red staining in PEMF+GSK group were between PEMF group and GSK group. CONCLUSIONS: PEMF may enhance the maturation and mineralization of rat cranial osteoblasts in vitro through IGF-1R/NO signaling pathway.


Assuntos
Campos Eletromagnéticos , Osteoblastos , Transdução de Sinais , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Óxido Nítrico/metabolismo , Osteoblastos/efeitos da radiação , Ratos , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos da radiação
9.
EMBO J ; 38(15): e101964, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267557

RESUMO

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1-1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor-promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1-1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Dietilnitrosamina/efeitos adversos , Regulação para Baixo , Glutationa Transferase/genética , Heptanoatos/metabolismo , Neoplasias Hepáticas/patologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Experimentais , Prognóstico , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Análise de Sobrevida
10.
Prostate ; 79(12): 1422-1438, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31269290

RESUMO

BACKGROUND: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. METHODS: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. RESULTS: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. CONCLUSIONS: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , MicroRNAs/biossíntese , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Receptor IGF Tipo 1/metabolismo , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Transdução de Sinais
11.
BMC Bioinformatics ; 20(1): 385, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288758

RESUMO

BACKGROUND: In cancer research, robustness of a complex biochemical network is one of the most relevant properties to investigate for the development of novel targeted therapies. In cancer systems biology, biological networks are typically modeled through Ordinary Differential Equation (ODE) models. Hence, robustness analysis consists in quantifying how much the temporal behavior of a specific node is influenced by the perturbation of model parameters. The Conditional Robustness Algorithm (CRA) is a valuable methodology to perform robustness analysis on a selected output variable, representative of the proliferation activity of cancer disease. RESULTS: Here we introduce our new freely downloadable software, the CRA Toolbox. The CRA Toolbox is an Object-Oriented MATLAB package which implements the features of CRA for ODE models. It offers the users the ability to import a mathematical model in Systems Biology Markup Language (SBML), to perturb the model parameter space and to choose the reference node for the robustness analysis. The CRA Toolbox allows the users to visualize and save all the generated results through a user-friendly Graphical User Interface (GUI). The CRA Toolbox has a modular and flexible architecture since it is designed according to some engineering design patterns. This tool has been successfully applied in three nonlinear ODE models: the Prostate-specific Pten-/- mouse model, the Pulse Generator Network and the EGFR-IGF1R pathway. CONCLUSIONS: The CRA Toolbox for MATLAB is an open-source tool implementing the CRA to perform conditional robustness analysis. With its unique set of functions, the CRA Toolbox is a remarkable software for the topological study of biological networks. The source and example code and the corresponding documentation are freely available at the web site: http://gitlab.ict4life.com/SysBiOThe/CRA-Matlab .


Assuntos
Algoritmos , Modelos Biológicos , Neoplasias/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Simulação por Computador , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Humanos , Cinética , Masculino , Camundongos , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Próstata/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
12.
Zhonghua Zhong Liu Za Zhi ; 41(7): 508-515, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357837

RESUMO

Objective: To investigate the expression levels and the mechanism of miR-126 and insulin like growth factor 1 receptor (IGF1R) in gastric cancer tissues and cells. Methods: The expression levels of miR-126 and IGF1R in 60 gastric cancer tissues and matched normal gastric tissues were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, respectively. The association of miR-126 expression with clinicopathology and prognosis of gastric cancer patients was further analyzed. CCK-8, soft agar assay, transwell assay were used to analyze the proliferation and invasion capacity of gastric cancer cells, respectively, while the dual luciferase reporter assay was used to determine the direct target of miR-126. Results: The expression of miR-126 was obviously correlated with lymphatic metastasis, distant metastasis and TNM stage of gastric cancer (all P<0.05). Cox multivariate analysis revealed that lymphatic metastasis, TNM stage, miR-126 and IGF-1R expression were independent risk factors for prognosis of gastric cancer patients (all P<0.05). The expression level of miR-126 in gastric cancer tissues was 2.01±0.23 significantly lower than 10.12±2.15 of normal gastric tissues (P<0.05). CCK-8 result showed that the absorbance values of MKN28 and BGC823 cells at 72 hours after transfected with miR-126 mimics were 1.06±0.05 and 1.01±0.09, respectively, significantly lower than 1.55±0.12 and 1.36±0.12 of the control group (all P<0.05). The clone numbers of MKN28 and BGC823 cells transfected with miR-126 mimics formed in the soft agar were 33±9 and 29±8, respectively, significantly lower than 76±13 and 71±11 of the control group (all P<0.05). Transwell assay showed that the invasived number of MKN28 and BGC823 cells transfected by miR-126 mimics was 98±12 and 89±8, respectively, significantly lower than 154±18 and 161±17 of the control group (all P<0.05). Double luciferase assay further clarified that miR-126 the 3'-untranslated region (3'-UTR) of IGF-1R, and inhibited its protein expression. CCK-8 results showed that overexpression of IGF-1R partially reversed the miR-126 induced proliferation inhibition in MKN28 (1.65±0.14 v. s. 0.98±0.11, P=0.003) and BGC823 cells (1.44 ±0.15 v. s. 0.89±0.10; P=0.006). Likewise, overexpression of IGF-1R partially reversed the miR-126-inhibited invasion of MKN28 (176±19 v. s. 101±14, P=0.005) and BGC823 cells (186±21 v. s. 92±9, P=0.002). Moreover, the inhibitory effects of miR-126 on proliferation were aggravated by silencing of IGF-1R in MKN28 (0.67±0.09 v. s. 0.99±0.12, P=0.021) and BGC823 cells (0.57±0.07 v. s. 0.92±0.12, P=0.012). Conclusion: miR-126 suppresses the proliferation and invasion of gastric cancer cells through targeting the 3'-UTR of IGF-1R and inhibiting its expression.


Assuntos
Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Receptor IGF Tipo 1/metabolismo , Neoplasias Gástricas/patologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Invasividade Neoplásica , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética
13.
J Pediatr Endocrinol Metab ; 32(7): 733-738, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31194684

RESUMO

Background Neonatal adrenoleukodystrophy (n-ALD) and X-linked ALD (X-ALD) patients present with demyelination, poor growth and progressive mental retardation. Growth factors are known to play a vital role in the development of children. Objective To examine the mitogenic activity of various growth factors in skin fibroblasts from n-ALD and X-ALD patients. Methods Skin fibroblast cultures from n-ALD and X-ALD patients, and controls were treated with 50 ng/mL of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) or insulin-like growth factor-1 (IGF-1) to examine DNA synthesis by 5-bromo-2'-deoxyuridine (BrdU) incorporation. Expression of receptors for PDGF, bFGF and IGF-1 was measured by western blotting. Serum levels of IGF-1 were assayed by enzyme-linked immunosorbent assay (ELISA). Results Fibroblasts from n-ALD and X-ALD patients had significantly (p < 0.01) less BrdU incorporation in response to fetal bovine serum (FBS). The mitogenic effect of PDGF, bFGF and IGF-1 was significantly lower in n-ALD as compared to control and X-ALD cells. X-ALD cells showed significant impairment in IGF-1-induced DNA synthesis. Expression of the FGF receptor (FGF-R) was significantly reduced in n-ALD cells. PDGF receptor remained unaffected, and IGF-1 receptor (IGF-1R) expression and serum IGF-1 levels were significantly (p < 0.01) reduced in n-ALD and X-ALD patients as compared to controls. Conclusions Growth factor activity differs in n-ALD and X-ALD patients, with marked impairment of IGF-1 function through receptor down-regulation.


Assuntos
Adrenoleucodistrofia/patologia , Biomarcadores/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Transtornos Peroxissômicos/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Adrenoleucodistrofia/tratamento farmacológico , Adrenoleucodistrofia/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Pré-Escolar , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Seguimentos , Humanos , Lactente , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Transtornos Peroxissômicos/tratamento farmacológico , Transtornos Peroxissômicos/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia
14.
Acta Biochim Biophys Sin (Shanghai) ; 51(7): 753-760, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31168597

RESUMO

The type-I insulin-like growth factor receptor (IGF-IR) is overexpressed in endometrial cancer. High IGF-IR expression was considered as an important prognostic factor for tumor progression. The purpose of this study was to investigate the role and molecular mechanism of IGF-IR inhibitor picropodophyllin (PPP) in the growth and development of endometrial cancer. High expression of IGF-IR was observed in endometrial cancer tissues, as well as in ECC-1 and KLE cell lines. PPP suppressed the number of clones of ECC-1 and KLE cell lines; however, it had no significant effect on HEC-1-A cell line, which expressed lower IGF-IR than ECC-1 and KLE cell lines. Furthermore, PPP reduced cell proliferation capacity, inhibited the IGF-IR mRNA expression, and suppressed protein phosphorylation of IGF-IR and Akt in the three cell lines. In addition, PPP inhibited the protein expression of survivin in KLE cell line after 1 h of exposure, though this effect did not last for prolonged time. In conclusion, IGF-IR was mostly overexpressed in type I endometrial cancer. High IGF-IR expression was an important prognostic factor of tumor progression. PPP mediated the down-regulation of IGF-IR phosphorylation and inhibited cell proliferation via the PI3K/Akt signal pathway. PPP may have the potential to become a clinical treatment target in endometrial carcinoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Podofilotoxina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Podofilotoxina/farmacologia , Prognóstico , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Survivina/genética , Survivina/metabolismo
15.
Growth Horm IGF Res ; 46-47: 24-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158782

RESUMO

OBJECTIVE: The objective of our study was to examine the direct action of insulin-like growth factor-1(IGF-1) signaling on energy homeostasis in myocytes. DESIGN: We studied the IGF-1 stimulation of mitochondrial uncoupling protein 3 (UCP3) expression in the HEK 293 derived cell line TSA201, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal myoblasts. We also investigated the direct effect of IGF-1 on the Insulin/IGF-1 receptor (IGF-1R)/phosphatidylinositol 3 (PI3)-Akt/forkhead box O4 (FOXO4) pathway using a combination of a reporter assay, semi-quantitative polymerase chain reaction, western blotting, and animal experiments. RESULTS: We demonstrated that IGF-1 regulates UCP3 expression via phosphorylation of FOXO4, which is a downstream signal transducer of IGF-1. UCP3 expression increased with activated FOXO4 in a dose-dependent manner. We also examined the functional FOXO4 binding site consensus sequences and identified it as the -1922 bp site in the UCP3 promoter region. UCP3 was also found to be concomitantly expressed with IGF-1 during differentiation of C2C12 myoblasts. Our animal experiments showed that high fat diet induced IGF-1 levels which likely influenced UCP3 expression in the skeletal muscle. CONCLUSION: Our findings demonstrate that that IGF-1 directly stimulates UCP3 expression via the IGF-1/IGF-1R/PI3-Akt/FOXO4 pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Músculo Esquelético/metabolismo , Mioblastos Esqueléticos/metabolismo , Proteína Desacopladora 3/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Proteína Desacopladora 3/genética
16.
Nat Commun ; 10(1): 2406, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160622

RESUMO

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.


Assuntos
Líquido Ascítico , Carcinoma/secundário , Adesão Celular , Hidrodinâmica , Células-Tronco Neoplásicas/metabolismo , Oligossacarídeos/metabolismo , Neoplasias Ovarianas/patologia , Selectina-P/metabolismo , Neoplasias Peritoneais/secundário , Animais , Carcinoma/metabolismo , Linhagem Celular Tumoral , Epitélio/metabolismo , Feminino , Fucosiltransferases/metabolismo , Células HEK293 , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Peritônio/metabolismo , Receptor IGF Tipo 1/metabolismo , Estresse Mecânico
17.
Gen Comp Endocrinol ; 281: 83-90, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31170402

RESUMO

The function of insulin-like growth factor (Igf) system in ovary has attracted much attention, but the role of Igf binding proteins (Igfbps) in ovary is still largely unknown. In this study, the role of Igfbps in oocyte maturation was investigated in zebrafish. The expression of all eight identified Igfbps except Igfbp6b could be detected in the adult ovary and exhibited differential expression profiles during folliculogenesis. The expression of several Igfbps is dynamically changed during oocyte maturation induced by human chorionic gonadotropin (hCG). By treatment of an Igfbps inhibitor NBI-31772 in vitro, the oocyte maturation could be stimulated in a clear dose-, time- and stage-dependent manner. Such effects were also observed by administration of NBI-31772 in vivo. Igfbps are differentially expressed in both follicular cells and oocytes, but the effect of NBI-31772 could only be found in intact follicles and not in the denuded oocytes. Previous studies have demonstrated that Igf3 is the major Igf member in regulating oocyte maturation of zebrafish. Interestingly, NBI-31772 could increase the effect of Igf3 on oocyte maturation. Furthermore, we found the effect of NBI-31772 on oocyte maturation could be blocked by an Igf type 1 receptor inhibitor BMS-536924 in vitro, suggesting the Igfbps can inhibit the oocyte maturation via Igf/Igf1r pathway. Together, we provided the first evidence in fish that Igfbps inhibit oocyte maturation of zebrafish.


Assuntos
Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Oócitos/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Catecóis/farmacologia , Gonadotropina Coriônica/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Isoquinolinas/farmacologia , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Biosci Biotechnol Biochem ; 83(10): 1858-1866, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31198094

RESUMO

Oxytocin, has various physiological functions that have been well studied and many that remain unknown. Here, we aimed to determine new physiological functions of oxytocin using Caenorhabditis elegans. Oxytocin treatment promoted the restoration of movement after heat stress and enhanced the viability under heat stress. However, oxytocin had no effect on the life span and only little effect on the oxidative stress tolerance. In contrast, oxytocin treatment didn't promote the restoration of movement or enhance the viability of deficient mutants of ntr-1/2, which is the gene encoding the oxytocin receptor. In addition, for mutants of daf-16, daf-2, tax-4, and some insulin-like peptides, the heat stress tolerance effect by oxytocin was canceled. Furthermore, oxytocin increased the expression levels of the DAF-16 target genes. Our results suggest that oxytocin treatment promoted the heat stress tolerance of C. elegans via the insulin/IGF-1 signaling pathway.


Assuntos
Adaptação Fisiológica/fisiologia , Caenorhabditis elegans/fisiologia , Resposta ao Choque Térmico , Insulina/metabolismo , Ocitocina/fisiologia , Transdução de Sinais/fisiologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo , Ocitocina/administração & dosagem , Receptor IGF Tipo 1/metabolismo
19.
BMC Res Notes ; 12(1): 347, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215459

RESUMO

OBJECTIVE: A dual inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor 1 receptor (IGF-1R), TAE226, was evaluated in a panel of cancer cell lines, MIA PaCa-2 human pancreatic tumor and 4T1 murine breast tumor models. The profiling data were generated during the drug discovery research prior to the first publication of TAE226 appeared in 2007 (Liu et al. in Mol Cancer Ther 6:1357-1367, 2007; Shi et al. in Mol Carcinog 46(6):488-496, 2007; Halder et al. in Cancer Res 67(22):10976-10983, 2007). RESULTS: In a panel of 37 cancer cell lines, TAE226 showed a mean GI50 value of 0.76 µmol/L. In the MIA PaCa-2 model, TAE226 inhibited phosphorylation of Y397-FAK and phosphorylation of S473-Akt as IGF-1R signaling in the cell culture in vitro and the tumor in mice. Oral administration of TAE226 induced tumor stasis at 30 mg/kg and tumor regression at 100 mg/kg in the subcutaneous tumor, and inhibited the orthotopic tumor growth in a dose-dependent manner. Similarly in the 4T1 model, TAE226 inhibited phosphorylation of Y397-FAK and S473-Akt in the cell culture in vitro and the tumor in mice. Oral administration of TAE226 inhibited the orthotopic tumor growth and metastasis to the lung in a dose-dependent manner. Thus, TAE226 represents a novel class of selective and small molecule kinase inhibitor with a potent in vivo activity.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Morfolinas/farmacologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Chem Pharm Bull (Tokyo) ; 67(5): 410-418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061365

RESUMO

2,4,5-Trichloro-6-((2,4,6-trichlorophenyl)amino)isophthalonitrile (SYD007) is a small molecule compound that was synthesized according to the structure of diarylamine. In this study, we evaluated the anti-bladder activities of SYD007, and determined its cytotoxic mechanism. We found that SYD007 exerted cytotoxicity to bladder cancer cells. Furthermore, SYD007 induced bladder cancer cell early apoptosis and arrested cell cycle. Mechanistically, SYD007 suppressed phosphorylated signal transducer and activator of transcription 3 (p-STAT3) (Tyr705) level in parallel with increases of p-extracellular signal-regulated kinase (ERK) and p-AKT. SYD007 significantly inhibited insulin-like growth factor 1 (IGF-1)-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in SYD007-treated cells, suggesting that SYD007 acted primarily at a posttranscriptional level. Using molecular docking analysis, SYD007 was identified as an IGF-1R inhibitor. In summary, we reported that SYD007 exerted anti-bladder activities, and these effects were partially due to inhibition of IGF-1R/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Nitrilos/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Nitrilos/síntese química , Nitrilos/química , Receptor IGF Tipo 1/metabolismo , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
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