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1.
Braz J Med Biol Res ; 52(6): e8399, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166382

RESUMO

Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , RNA Longo não Codificante/genética , Receptores de Somatomedina/genética , Apoptose , Linhagem Celular Tumoral , Regulação para Baixo/genética , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , RNA Longo não Codificante/metabolismo , Receptores de Somatomedina/metabolismo , Transdução de Sinais
2.
Medicine (Baltimore) ; 98(19): e15467, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083179

RESUMO

BACKGROUND: Insulin-like growth factor receptor 1 (IGF-1R) is a key player in a wide array of pathological processes, while the prognostic role of IGF-1R in lung cancer remains controversial. METHODS: We conducted a meta-analysis to evaluate the prognostic value of IGF-1R in lung cancer. We searched for recent studies on the expression of IGF-1R and extracted prognostic lung cancer data from the articles. RESULTS: Eventually, 22 studies with 3859 patients were analyzed in our meta-analysis. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to quantify the ability of IGF-1R to predict survival. The results indicated that IGF-1R positive expression was associated with an unfavorable disease-free survival (DFS) in non-small cell lung cancer (NSCLC) patients on univariate analysis (HR = 1.24, 95% CI: 1.00-1.55, P = .054) and multivariate analysis (HR = 1.49, 95% CI: 1.01-2.21, P = .045), but there was no significant difference in the relationship between IGF-1R positive expression and overall survival (OS) on univariate analysis (HR = 1.04, 95% CI: 0.86-1.25, P = .712) and multivariate analysis (HR = 0.89, 95% CI: 0.57-1.39, P = .602). IGF-1R mRNA expression related to OS was obtained in 2 studies, with the pooled HR being 1.663 (95% CI: 1.071-2.583, P = .024). For IGF-1R expression and small cell lung cancer (SCLC), the conclusion was not statistically significant, with the pooled HR being 1.22 (95% CI: 0.66-2.27, P = .524). CONCLUSIONS: Our results indicate that high expression of IGF-1R predicts poor DFS in NSCLC, yet it does not predict poor OS in NSCLC and SCLC. IGF-1R may be a useful predictor of outcomes in patients with NSCLC.


Assuntos
Neoplasias Pulmonares/diagnóstico , Receptores de Somatomedina/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Prognóstico
3.
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
4.
BMC Cancer ; 19(1): 405, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035970

RESUMO

BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action. METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified. RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p. CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Transdução de Sinais/genética , Tumor de Wilms/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Criança , Progressão da Doença , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia
5.
J BUON ; 24(1): 256-266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941978

RESUMO

PURPOSE: Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio. METHODS: The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR. RESULTS: The confirmed prognostic factors for overall survival (OS) were pTNM T (p<0.01), pTNM N (p<0.05), clinical stage (p<0.05), type of surgery (p<0.01) and histopathological (HP) tumor type (p<0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS. CONCLUSIONS: In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.


Assuntos
Tumor Carcinoide/mortalidade , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Neoplasias Pulmonares/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Somatomedina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Tumor Carcinoide/genética , Tumor Carcinoide/metabolismo , Tumor Carcinoide/patologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Somatomedina/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Adulto Jovem , Proteína X Associada a bcl-2/genética
6.
Am J Chin Med ; 47(3): 675-689, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30966770

RESUMO

Pancreatic cancer cells overexpress the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R). Activating these receptors, insulin and insulin-like growth factor-1 increase the growth and glycolysis of pancreatic cancer cells. The high glycolysis in pancreatic cancer cells increases whole-body energy expenditure and is therefore involved in the pathogenesis of cancer cachexia. The antagonism of IR and IGF1R may sabotage pancreatic cancer cells and attenuate cancer cachexia. Previous studies have shown that the intracellular regulating system of IR/IGF1R may be functionally interrelated to another intracellular system whose master regulator is hypoxia-inducible factor-1 (HIF-1). In this study, we investigated how the IR/IGF1R and HIF-1 systems are interrelated in pancreatic cancer cells. We also investigated whether a phytochemical, penta-O-galloyl- ß -D-glucose ( ß -PGG), antagonizes IR/IGF1R, sabotages pancreatic cancer cells and alleviates cancer cachexia. We found in MiaPaCa2 pancreatic cancer cells that IR/IGF1R activation increased both the α -subunit of HIF-1 and caveolin-1. This result suggests that IR/IGF1R, HIF-1 α , and caveolin-1 may constitute a feed-forward loop to mediate the effect of IR/IGF1R activation. ß -PGG inhibited IR/IGF1R activity and decreased glycolytic enzymes in MiaPaCa2 and Panc-1 pancreatic cancer cells. When MiaPaCa2 cells were transplanted in athymic mice, their growth was inhibited by ß -PGG or by a HIF-1 α inhibitor, rhein. ß -PGG and rhein also decreased glycolytic enzymes in the tumor grafts and reduced liver gluconeogenesis, skeletal-muscle proteolysis and fat lipolysis in the tumor carriers. Cancer-induced body-weight loss, however, was prevented by ß -PGG but not rhein. In conclusion, ß -PGG combats pancreatic cancer cells and cures cancer cachexia.


Assuntos
Caquexia/tratamento farmacológico , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Animais , Caquexia/etiologia , Caveolina 1/metabolismo , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neoplasias Pancreáticas/complicações , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/metabolismo , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Células Tumorais Cultivadas
7.
EBioMedicine ; 41: 597-609, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30852161

RESUMO

BACKGROUND: The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF. METHODS: From two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized. FINDINGS: In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities. INTERPRETATION: This study revealed that the FF-IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions. FUND: The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01).


Assuntos
Líquido Folicular/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Animais , Carcinogênese , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/transplante , Tubas Uterinas/citologia , Feminino , Líquido Folicular/química , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Proteína Plasmática A Associada à Gravidez/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
8.
Bull Exp Biol Med ; 166(5): 641-645, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30903488

RESUMO

Metastatic cascade is associated with the process of epithelial-mesenchymal transition accompanied by changes in cell proliferation, migration, adhesion, and invasiveness mediated by the insulin-like growth factor (IGF) signal pathway. IGFBP6 protein binds IGF and prevents its interaction with receptors. IGFBP6 gene knockdown through RNA-interference inhibits cell migration and increased the rate of proliferation of breast cancer MDA-MB-231 cells. IGFBP6 knockdown cells are characterized by increased expression of MIR100 and MIRLET7A2 genes encoding hsa-miR-100-3p, hsa-miR-100-5p, hsa-let-7a-5p, and hsa-let-7a-2-3p miRNA. The target genes of these microRNAs are IGF2, IGF1R, INSR, and CCND1 associated with IGF signaling pathway and proliferative and migratory activity during the metastatic cascade. A significant decrease in the expression of INSR and CCND1 genes was demonstrated by PCR and microarray analysis.


Assuntos
Antígenos CD/metabolismo , Ciclina D1/metabolismo , MicroRNAs/metabolismo , Receptor de Insulina/metabolismo , Receptores de Somatomedina/metabolismo , Antígenos CD/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/genética , Receptor de Insulina/genética , Receptores de Somatomedina/genética
9.
J Pharmacol Sci ; 139(3): 186-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30850243

RESUMO

BACKGROUND: Local anesthetics (LAs) may generate neurotoxicity in neurons. In the current study, we explored the mechanisms by which microRNA-132 (miR-132) regulated the neurotoxicity of human neuroblastoma cells (SH-SY5Y) induced by bupivacaine (BUP). METHODS: CCK-8, flow cytometry, EdU detection, qRT-PCR and western blotting were used to explore the cell viability, apoptosis and gene expression, respectively. RESULTS: In this study, we found that 600 µM BUP dramatically inhibited SH-SY5Y cells viability. In addition, BUP induced cell apoptosis and neurotoxicity via increasing active caspase-3 and cleaved PARP1 levels. More importantly, the level of miR-132 was significantly up-regulated in BUP-treated cells, which was significantly reversed by miR-132 inhibitor. In addition, dual-luciferase assay indicated IGF1R was the directly binding target of miR-132 in cells. Our study further indicated that the level of IGF1R was markedly decreased by BUP interference, while miR-132 inhibitor exerted the opposite effect. Furthermore, BUP induced apoptosis and neurotoxicity in SH-SY5Y cells were attenuated by IGF1, which further confirmed IGF1R was the downstream target of BUP in SH-SY5Y cells. CONCLUSION: In the present study, miR-132 played important roles in regulating BUP-induced neurotoxicity through IGF1R and may act as a promising molecular target for the treatment of human neurotoxicity induced by BUP.


Assuntos
Anestésicos Locais/toxicidade , Bupivacaína/toxicidade , MicroRNAs/genética , Síndromes Neurotóxicas/etiologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Neuroblastoma/metabolismo , Síndromes Neurotóxicas/genética , Receptores de Somatomedina/metabolismo , Regulação para Cima/genética
10.
Molecules ; 24(3)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754629

RESUMO

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC50's between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Neoplasias Colorretais/metabolismo , Dasatinibe/farmacologia , Redes Reguladoras de Genes/efeitos dos fármacos , Pirazóis/farmacologia , Triazinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Células HCT116 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Terapia de Alvo Molecular , Fosfoproteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Int J Mol Sci ; 20(3)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754657

RESUMO

Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Metabolismo Energético , Insulina/metabolismo , Organogênese , Receptor de Insulina/metabolismo , Animais , Humanos , Receptores de Somatomedina/metabolismo
12.
Int J Oncol ; 54(4): 1345-1356, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720056

RESUMO

Cetuximab is a monoclonal antibody developed to inhibit the binding of growth factors and the subsequent activation of epidermal growth factor receptor (EGFR). Triple­negative breast cancer (TNBC) is resistant to cetuximab treatment. The aim of the present study was to examine the partial agonistic properties of cetuximab, which not only blocks ligand binding, but also partially triggers EGFR activation, which may lead to cetuximab resistance in TNBC. The phosphorylation of growth factor receptors and their signalling pathways were evaluated by determining the phosphorylation of EGFR, insulin­like growth factor receptor (IGF­1R), vascular endothelial growth factor receptor (VEGFR)­2, Src kinase, phosphoinositide­3­kinase (PI3K), extracellular signal­regulated kinase (ERK1/2) and serine/threonine­specific protein kinase (Akt) and the degradation of EGFR, and by assessing the morphology and proliferation of MDA­MB­231 and MDA­MB­468 cells. Cetuximab treatment led to the phosphorylation of EGFR, VEGFR­2, IGF­1R and downstream signalling molecules, Src kinase and PI3K in these cells, as well as Akt in the MDA­MB­231 cells. The cetuximab­mediated phosphorylation of IGF­1R, VEGFR­2 and Akt was inhibited by the EGFR kinase inhibitor, AG1478, and the Src kinase inhibitor, PP2. Cetuximab treatment led to the degradation of EGFR. The cetuximab­induced phosphorylation and EGFR degradation were less prominent compared with those induced by EGF. Cetuximab partially inhibited EGF­mediated responses. Cetuximab, similar with EGF, altered cellular morphology in a serum­free medium. In both cell lines, the Src kinase inhibitor enhanced the cetuximab­induced anti­proliferative response. These results indicate that cetuximab exerts a partial agonistic effect on EGFR, which activates Src kinase and subsequently transactivates IGF­1R and VEGFR­2. This partial agonistic property is likely one of the mechanisms underlying the resistance of TNBC to cetuximab.


Assuntos
Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Mama Triplo Negativas/metabolismo , Quinases da Família src/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/agonistas , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
J Pediatr Hematol Oncol ; 41(2): 96-104, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30688831

RESUMO

OBJECTIVE: Hyperglycemia increases the risk of early recurrence and high mortality in some adult blood cancers. In response to increased glucose levels, insulin is secreted, and several studies have shown that insulin-induced AKT signaling can regulate tumor cell proliferation and apoptosis. The AKT pathway is aberrantly activated in adult acute lymphoblastic leukemia (ALL), but the mechanisms underlying this activation and its impact in pediatric patients with ALL are unclear. MATERIALS AND METHODS: We evaluated the insulin-induced chemoresistance and AKT pathway activation by measuring cell proliferation, apoptosis, and other parameters in ALL cell lines (Jurkat and Reh cells), as well as in primary pediatric leukemic cell samples, after culture with insulin, the chemotherapeutic drugs daunorubicin (DNR), vincristine (VCR), and L-asparaginase (L-Asp), or anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody. RESULTS: DNR, VCR, and L-Asp-induced toxicity in Jurkat and Reh cells was reduced in the presence of insulin. DNR promoted cell proliferation, whereas DNR, VCR, and L-Asp all reduced apoptosis in both cell lines cotreated with insulin compared with that in cell lines treated with chemotherapeutics alone (P<0.05). Furthermore, addition of an anti-IGF-1R monoclonal antibody promoted apoptosis, downregulated IGF-1R expression, and decreased the phosphorylation of AKT, P70S6K, and mTOR intracellular signaling pathway proteins in both cell lines, as well as in primary cultures (P<0.05). CONCLUSIONS: Our results suggest that insulin-induced chemoresistance and activation of the AKT signaling pathway in pediatric ALL cells.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Insulina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Antineoplásicos Imunológicos/farmacologia , Asparaginase/farmacologia , Criança , Pré-Escolar , Daunorrubicina/farmacologia , Feminino , Humanos , Células Jurkat , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Vincristina/farmacologia
14.
Int J Oncol ; 54(3): 807-820, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664191

RESUMO

Accumulating evidence has indicated that the dysregulation of microRNAs (miRNAs) is involved in the pathogenesis o retinoblastoma (RB); however, the potential role of miR­98 in RB remains elusive. In the present study, it was demonstrated that miR­98 is downregulated in RB tissues and cell lines, and its expression significantly associated with clinicopathological features, including differentiation, N classification and largest tumor base; patients with low miR­98 expression levels exhibited significantly poorer overall survival. Overexpression of miR­98 was suggested to suppress RB cell growth, migration and invasion. In addition, insulin­like growth factor­1 receptor (IGF1R), a well­reported oncogene, was identified as a potential target of miR­98 via a luciferase assay, reverse transcription­quantitative polymerase chain reaction and western blotting. Correlation analysis revealed a significantly negative correlation between miR­98 and IGF1R expression in tumor tissues (n=60). In addition, the results of the present study demonstrated that IGF1R function as an oncogene by promoting RB cell viability, migration and invasion. Furthermore, restoration of IGF1R was observed to reverse the anticancer effects of miR­98 on RB cell viability, migration and invasion. Importantly, the findings of the present study indicated that miR­98 suppressed RB cell growth and metastasis by inhibiting the IGF1R/k­Ras/Raf/mitogen activated protein kinase kinase/extracellular signal­regulated kinase signaling pathway. Collectively, the present study proposed that miR­98 may serve as a novel prognostic biomarker and therapeutic target in the treatment of RB.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Receptores de Somatomedina/metabolismo , Retinoblastoma/mortalidade , Retinoblastoma/patologia , Transdução de Sinais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , MicroRNAs/genética , Invasividade Neoplásica , Ligação Proteica , Receptores de Somatomedina/genética , Retinoblastoma/genética , Retinoblastoma/metabolismo , Taxa de Sobrevida
15.
Int J Mol Med ; 43(3): 1505-1512, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628637

RESUMO

Dysregulation of microRNAs (miRs) is implicated in the carcinogenesis of various types of malignant tumor by manipulating cell growth and apoptosis. Abnormal expression of miR­320a is involved in tumorigenesis of many types of cancer. The potential association of miR­320a and the possible regulatory mechanisms in endometrial carcinoma is rarely elucidated. In the present study, it was demonstrated that miR­320a expression was decreased in endometrial carcinoma tissues and cell lines. The present results also indicated that overexpression of miR­320a suppressed cell proliferation through inducing G2/M phrase arrest and apoptosis. Insulin­like growth factor receptror­1 (IGF­1R) was verified to be the potential target of miR­320a by computational analysis and luciferase reporter assays. In addition, overexpression of miR­320a reduced endogenous IGF­1R expression in cells. Furthermore, it was demonstrated that upregulation of miR­320a inhibited phosphorylated (p)­protein kinase B and p­mechanistic target of rapamycin activation and promoted B cell lymphoma­2­associated death promoter expression. Reintroduction of IGF­1R into miR­320a­overexpressed cells antagonized the impact of miR­320a on its downstream protein, which demonstrated that the tumor suppressive role of miR­320a in endometrial carcinoma is exerted by the signal pathway mediated by IGF­1R. It was therefore concluded that miR­320a served an anti­tumor role on endometrial carcinoma through the regulation of IGF­1R, and miR­320a may be used as the target for the gene therapy of endometrial carcinoma.


Assuntos
Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/genética , Interferência de RNA , Receptores de Somatomedina/genética , Adulto , Idoso , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias do Endométrio/metabolismo , Feminino , Genes Reporter , Humanos , Pessoa de Meia-Idade , Fosforilação , Receptores de Somatomedina/metabolismo
16.
Phytomedicine ; 57: 1-8, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30668312

RESUMO

BACKGROUND: Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet. HYPOTHESIS: The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR). METHODS/STUDY DESIGN: The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24  h) for 2  h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10  mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting. RESULTS: Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-xL, p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models. CONCLUSION: In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.


Assuntos
Angiotensina II/efeitos adversos , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Hipertensão/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Angiotensina II/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Ratos Endogâmicos SHR , Ratos Wistar , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
BMC Cancer ; 19(1): 62, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642298

RESUMO

BACKGROUND: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells. METHODS: Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC. RESULTS: CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rß levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rß/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities. CONCLUSIONS: Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.


Assuntos
Neoplasias Ósseas/etiologia , Neoplasias Ósseas/metabolismo , Proteína Rica em Cisteína 61/genética , Transição Epitelial-Mesenquimal/genética , Osteossarcoma/etiologia , Osteossarcoma/metabolismo , Receptores de Somatomedina/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias Ósseas/patologia , Caderinas/metabolismo , Adesão Celular/genética , Comunicação Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proteína Rica em Cisteína 61/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/secundário , Sistema de Sinalização das MAP Quinases , Camundongos , Osteossarcoma/patologia
18.
Mol Genet Metab ; 126(3): 259-265, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639046

RESUMO

The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of both IGF1 and IGF2. In recent years, evidence has accumulated showing that, in addition to its classical cell-surface distribution, IGF1R translocates to cell nucleus via an apparently SUMO-1-dependent mechanism. While the role of IGF1R in nucleus has not yet been settled, available information suggests that the nuclear receptor displays activities usually linked to transcription factors, including DNA binding and transcription regulation. To gain insight into the biological pathways associated with nuclear IGF1R action we conducted a mass spectrometry-based proteomic analysis aimed at identifying interactors of IGF1R in nucleus of both benign and malignant breast cells. The nucleolar NOM1 molecule belongs to a family of proteins that contain the middle domain of eukaryotic initiation factor 4G (MIF4G) and/or interaction module (MA3), and functions in translation, cell growth and proliferation. Using a combination of co-immunoprecipitation and silencing assays we provide evidence of a complex, bi-directional interplay between nuclear IGF1R and nucleolar protein NOM1. Inhibition of nuclear IGF1R translocation by dansylcadaverine reduced NOM1 levels in nuclei of MCF7 cells. On the other hand, IGF1R overexpression enhanced NOM1 levels in the nuclear fraction. Of interest, NOM1 silencing led to a major increase in IGF1R biosynthesis. In summary, results are consistent with a physiologically-relevant interplay between the nuclear IGF1 signaling pathway and nucleolar protein NOM1.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores de Somatomedina/metabolismo , Transdução de Sinais , Linhagem Celular , Núcleo Celular , Proliferação de Células , Inativação Gênica , Humanos , Fator de Crescimento Insulin-Like I/genética , Células MCF-7 , Proteínas Nucleares/antagonistas & inibidores , Fosforilação , Ligação Proteica , Proteômica , RNA Interferente Pequeno , Proteínas de Ligação a RNA/antagonistas & inibidores , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética
19.
Biochim Biophys Acta Biomembr ; 1861(4): 819-826, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682326

RESUMO

The plasma membrane is a dynamic environment with a complex composition of lipids, proteins, and cholesterol. Areas enriched in cholesterol and sphingolipids are believed to form lipid rafts, domains of highly ordered lipids. The unique physical properties of these domains have been proposed to influence many cellular processes. Here, we demonstrate that the activation of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) depends critically on the structures of membrane sterols. IR and IGF1R autophosphorylation in vivo was inhibited by cholesterol depletion, and autophosphorylation was restored by the replacement with exogenous cholesterol. We next screened a variety of sterols for effects on IR activation. The ability of sterols to support IR autophosphorylation was strongly correlated to the propensity of the sterols to form ordered domains. IR autophosphorylation was fully restored by the incorporation of ergosterol, dihydrocholesterol, 7-dehydrocholesterol, lathosterol, desmosterol, and allocholesterol, partially restored by epicholesterol, and not restored by lanosterol, coprostanol, and 4-cholesten-3-one. These data support the hypothesis that the ability to form ordered domains is sufficient for a sterol to support ligand-induced activation of IR and IGF1R in intact mammalian cells.


Assuntos
Microdomínios da Membrana/metabolismo , Receptores de Somatomedina/metabolismo , Esteróis/metabolismo , Células HEK293 , Humanos , Microdomínios da Membrana/química , Fosforilação , Receptores de Somatomedina/química , Esteróis/química , Esteróis/farmacologia , Relação Estrutura-Atividade
20.
Iran Biomed J ; 23(1): 21-33, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30041514

RESUMO

Background: Targeted co-delivery of siRNA and a chemotherapeutic drug is an attractive approach to cancer drug design and treatment. This study was carried out to design an anti-Mucin1 aptamer (Apt)-conjugated chitosan nanoparticle (NP) for targeted co-delivery of insulin-like growth factor receptor 1 (IGF-1R) Silencer siRNA and docetaxel (DTX) to SKBR3 cells. Methods: Characterization of nano-drugs, cellular uptake of NPs, cell viability, and gene expression studies were evaluated based on metastatic breast cancer cells. Results: The results of this study showed that NPs had spherical and smooth morphology with 110-118 nm in size and had positive zeta potential (12-14 mV). siRNA and DTX were considerably loaded into NPs. The appropriate conjugation of the Apt to the NPs was affirmed by gel electrophoresis. The Apt-conjugated NPs were observed to enhance the cellular uptake of NPs into the SKBR3 cells. Although the combination treatment significantly decreased the cell viability of SKBR3 cells, the augmentative effect was observed when Apt was conjugated to NPs. Furthermore, Apt-conjugated NPs dramatically reduced the genetic expression of IGF-1R, signal transducers and activators of transcription 3 (STAT3), matrix metalloproteinases (MMP9), and vascular growth factor (VEGF). Conclusion: The targeted NPs may augment the targeting of pathways involved in tumorigenesis and metastasis of breast cancer. Therefore, more animal model experiments are needed to further clarify the efficacy and safety of this functionalized nanodrug.


Assuntos
Aptâmeros de Nucleotídeos/química , Neoplasias da Mama/patologia , Quitosana/química , Docetaxel/farmacologia , Mucina-1/metabolismo , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Receptores de Somatomedina/metabolismo , Animais , Neoplasias da Mama/genética , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Docetaxel/administração & dosagem , Liberação Controlada de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Heparina/química , Humanos , Nanopartículas/ultraestrutura , Metástase Neoplásica , Tamanho da Partícula , Soro/metabolismo , Eletricidade Estática
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