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1.
N Engl J Med ; 382(4): 341-352, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31971679

RESUMO

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Diplopia/tratamento farmacológico , Método Duplo-Cego , Esquema de Medicação , Exoftalmia/tratamento farmacológico , Oftalmopatia de Graves/diagnóstico por imagem , Humanos , Análise de Intenção de Tratamento , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Órbita/diagnóstico por imagem , Receptor IGF Tipo 1/imunologia , Autorrelato
2.
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
3.
Nat Commun ; 10(1): 3601, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399589

RESUMO

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching.


Assuntos
Predisposição Genética para Doença/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Camundongos , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
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
5.
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
6.
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
7.
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
8.
Endocrinology ; 160(6): 1439-1447, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31002310

RESUMO

DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressing short hairpin RNA in vitro or treatment with the IGF-1R phosphorylation inhibitor picropodophyllotoxin (PPP) in vitro and in vivo led to markedly induced GH receptor (GHR) abundance, rendering cells more responsive to GH actions. Suppressing IGF-1R triggered DNA damage in both normal human colon cells and three-dimensional human intestinal organoids. DNA damage was further increased when cells with disrupted IGF-1R were treated with GH. Because GH induction of DNA damage accumulation appeared to be mediated not by IGF-1R but probably by more abundant GH receptor expression, we injected athymic mice with GH-secreting xenografts and then treated them with PPP. In these mice, high circulating GH levels were associated with increased colon DNA damage despite disrupted IGF-1R activity (P < 0.01), whereas GHR levels were also induced. Further confirming that GH effects on DNA damage are directly mediated by GHR signaling, GHR-/- mice injected with PPP did not show increased DNA damage, whereas wild-type mice with intact GHR exhibited increased colon DNA damage in the face of IGF-1 signaling suppression. The results indicate that GH directly induces DNA damage independent of IGF-1.


Assuntos
Colo/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Animais , Linhagem Celular Tumoral , Colo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Exp Neurol ; 312: 72-81, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30503192

RESUMO

Disruption of the blood-brain barrier results in the formation of edema and contributes to the loss of neurological function following intracerebral hemorrhage (ICH). This study examined insulin-like growth factor-1 (IGF-1) as a treatment and its mechanism of action for protecting the blood-brain barrier after ICH in mice. 171 Male CD-1 mice were subjected to ICH via collagenase or autologous blood. A dose study for recombinant human IGF-1 (rhIGF-1) was performed. Brain water content and behavioral deficits were evaluated at 24 and 72 h after the surgery, and Evans blue extravasation and hemoglobin assay were conducted at 24 h. Western blotting was performed for the mechanism study and interventions were used targeting the IGF-1R/GSK3ß/MEKK1 pathway. rhIGF-1 reduced edema and blood-brain barrier permeability, and improved neurobehavior outcomes. Western blots showed that rhIGF-1 reduced p-GSK3ß and MEKK1 expression, thereby increasing occludin and claudin-5 expression. Inhibition and knockdown of IGF-1R reversed the therapeutic benefits of rhIGF-1. The findings within suggest that stimulation of the IGF-1R is a therapeutic target for ICH which may lead to improved neurofunctional and blood-brain barrier protection.


Assuntos
Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar/fisiologia , Hemorragia Cerebral/metabolismo , Fator de Crescimento Insulin-Like I/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Injeções Intraventriculares , Masculino , Camundongos , RNA Interferente Pequeno/administração & dosagem , Receptor IGF Tipo 1/agonistas , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo
10.
Exp Eye Res ; 178: 148-159, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267656

RESUMO

Teleosts are unique in their ability to undergo persistent neurogenesis and to regenerate damaged and lost retinal neurons in adults. This contrasts with the human retina, which is incapable of replacing lost retinal neurons causing vision loss/blindness in the affected individuals. Two cell populations within the adult teleost retina generate new retinal neurons throughout life. Stem cells within the ciliary marginal zone give rise to all retinal cell types except for rod photoreceptors, which are produced by the resident Müller glia that are located within the inner nuclear layer of the entire retina. Understanding the mechanisms that regulate the generation of photoreceptors in the adult teleost retina may ultimately aid developing strategies to overcome vision loss in diseases such as retinitis pigmentosa. Here, we investigated whether photic deprivation alters the proliferative capacity of rod precursor cells, which are generated from Müller glia. In dark-adapted retinas, rod precursor cell proliferation increased, while the number of proliferating Müller glia and their derived olig2:EGFP-positive neuronal progenitor cells was not significantly changed. Cell death of rod photoreceptors was excluded as the inducer of rod precursor cell proliferation, as the number of TUNEL-positive cells and l-plastin-positive microglia in both the outer (ONL) and inner nuclear layer (INL) remained at a similar level throughout the dark-adaptation timecourse. Rod precursor cell proliferation in response to dark-adaptation was characterized by an increased number of EdU-positive cells, i.e. cells that were undergoing DNA replication. These proliferating rod precursor cells in dark-adapted zebrafish differentiated into rod photoreceptors at a comparable percentage and in a similar time frame as those maintained under standard light conditions suggesting that the cell cycle did not stall in dark-adapted retinas. Inhibition of IGF1-receptor signaling reduced the dark-adaptation-mediated proliferation response; however, caloric restriction which has been suggested to be integrated by the IGF1/growth hormone signaling axis did not influence rod precursor cell proliferation in dark-adapted retinas, as similar numbers were observed in starved and normal fed zebrafish. In summary, photic deprivation induces cell cycle entry of rod precursor cells via IGF1-receptor signaling independent of Müller glia proliferation.


Assuntos
Proliferação de Células/efeitos da radiação , Luz , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células-Tronco/citologia , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Adaptação à Escuridão , Células Ependimogliais/citologia , Células Ependimogliais/metabolismo , Marcação In Situ das Extremidades Cortadas , Injeções Intraperitoneais , Neurogênese/fisiologia , Estimulação Luminosa , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células-Tronco/metabolismo , Taurina/farmacologia , Peixe-Zebra
11.
Int J Impot Res ; 31(1): 1-8, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30072768

RESUMO

To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n = 7). The third group received BCNI and Pio treatment (BCNI + Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI + Pio + JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rß (p-IGF-1Rß), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI + Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI + Pio + JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rß was observed in the BCNI + Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI + Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rß. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.


Assuntos
Disfunção Erétil/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/complicações , Pioglitazona/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Disfunção Erétil/etiologia , Masculino , Compressão Nervosa , Óxido Nítrico Sintase Tipo I/metabolismo , Fosforilação/efeitos dos fármacos , Pioglitazona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
12.
Endocr Rev ; 40(1): 236-267, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30215690

RESUMO

Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.


Assuntos
Anticorpos Monoclonais/farmacologia , Oftalmopatia de Graves , Receptor IGF Tipo 1 , Receptores da Tireotropina , Animais , Anticorpos Monoclonais Humanizados , Oftalmopatia de Graves/tratamento farmacológico , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/metabolismo , Humanos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Receptor IGF Tipo 1/metabolismo , Receptores da Tireotropina/metabolismo
13.
Brain Res Bull ; 144: 140-148, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217735

RESUMO

Sevoflurane is an experimental potent yet volatile anesthesia agent characterized by a low blood/gas partition coefficient. However, exposure to sevoflurane in neonatal mice has been speculated to result in learning deficits and abnormal social behavior. The aim of the present study was to investigate the relationship between sevoflurane and miR-96, in an attempt to identify the means by which it mediates IGF1R to influence the cognitive dysfunction (CD) in neonatal rats. Relationship between differentially expressed miRNAs and sevoflurane concentration was identified. The potential underlying regulatory mechanisms involved with sevoflurane were investigated through the administration of varying concentrations of the agent (1%, 2% and 4%), combined with miR-96 mimic or an inhibitor. A target prediction program was utilized, while the luciferase activity was determined in order to verify whether miR-96 targets IGF1R. The mRNA and protein levels of IGF1R, Bcl-2, Bax, and caspase-3 were measured followed by the determination of hippocampal neuron apoptosis. Learning and memory performance was assessed using the Morris water maze (MWM) test and step-down test. The obtained results highlighted a positive correlation between miR-96 and the concentration of sevoflurane, while miR-96 was confirmed to negatively target IGF1R. Our analyses indicated that 4% sevoflurane had a significantly stronger effect on reducing the levels of IGF1R and Bcl-2, while elevating the levels of miR-96, Bax and caspase-3 more so than that of 1% or 2% sevoflurane, which resulted in increased hippocampal neuron apoptosis but diminished the learning and memory performance of the rats. The addition of miR-96 mimic was demonstrated to exacerbate the influence of sevoflurane on hippocampal neurons as well as the cognitive function of the rats. The key findings of our study highlighted the role of miR-96 in the potential mechanism of sevoflurane anesthesia-induced CD in neonatal rats through the downregulation of IGF1R.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/genética , MicroRNAs/metabolismo , Anestésicos Inalatórios/farmacologia , Animais , Animais Recém-Nascidos/genética , Apoptose/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Éteres Metílicos/farmacologia , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Sevoflurano/farmacologia
14.
Proc Natl Acad Sci U S A ; 115(51): E12063-E12072, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30509997

RESUMO

Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.


Assuntos
Artrite Reumatoide/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto , Idoso , Animais , Artrite Reumatoide/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Giro Denteado/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Pessoa de Meia-Idade , Neurogênese/efeitos dos fármacos , Dor , Medição da Dor , Fosforilação , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Regulação para Cima , Adulto Jovem
15.
Metallomics ; 10(11): 1570-1575, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30349927

RESUMO

Selenium (Se) deficiency impairs the development and function of immune system in human beings and animals. We investigated the effect and molecular mechanism of Se deficiency on spleen development in chicken. The concentration of Se in blood and spleen, the spleen weight and splenocyte number, the histological characteristics of spleen, the concentration of growth factors in serum, the transcription level of growth factor receptor gene and the activity of growth and proliferation pathway in spleen were investigated. We found that the growth of the spleen and the splenocyte number were significantly lower in the chicken fed with Se-deficient diet for 21 and 35 days. The ELISA and qRT-PCR results showed that the serum IGF-I concentration and the transcription level of IGF1R gene in spleen were significantly lower in the SD group. The Western blotting and immunohistochemistry results showed that Se deficiency could deactivate the PI3K/Akt/mTOR pathway in spleen. In summary, the results indicated that Se deficiency decreases the growth rate of spleen and the number of splenic lymphocytes by deactivating the IGF-1R/PI3K/Akt/mTOR pathway.


Assuntos
Transtornos do Crescimento/etiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptor IGF Tipo 1/antagonistas & inibidores , Selênio/deficiência , Baço/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Galinhas , Regulação da Expressão Gênica , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Baço/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Drug Des Devel Ther ; 12: 2887-2896, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254418

RESUMO

Objective: To explore the anti-inflammatory mechanism of IGF1R inhibitor in diabetic nephropathy. Methods: C57/BL6 mice were reared with high-fat diet for 8 weeks, then were injected 30 mg/kg streptozotocin intraperitoneally to induce type 2 diabetes. After 8 weeks, the type 2 diabetes nephropathy model was successfully set up the different drugs were administrated to mice with diabetes (insulin 1-2 U/day, benazepril 10 mg/kg per day intragastrically, IGF-1R inhibitor 30 mg/kg per day intragastrically). After 8 weeks drugs administration, all mice were collected the kidney tissue, measured levels of inflammatory factor (F4/80, TLR4and CD68) and fibrosis markers(αSMA, E-cadherin and SR) using immunohistochemistry and in situ hybridization. Results: The type 2 diabetes nephropathy model was built successfully, which along with increased urinary protein excretion rate and increased inflammatory infiltration, and the correlation was characterized by increased CD68+, F4/80+ cells and increased TLR4, αSMA, SR expression. IGF-1R inhibitors reversed this changes, but benazepril and insulin were without significant changes. The insulin decreased the expression level of IGF-1, and increased the levels of suppressor of cytokine signaling 2 (SOCS2). Benazepril and IGF-1R inhibitor were no significant changes like insulin. Conclusion: Inhibition of IGF1R was a more effective choice for inflammation treatment than Ben or Ins in diabetic kidney disease (DKD). The IGF1R inhibitor blocked pathological changes induced by the over-expression of IGF1 in DKD without up-regulating SOCS2 protein levels.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Imidazóis/farmacologia , Inflamação/tratamento farmacológico , Piridinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Imidazóis/química , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/química , Receptor IGF Tipo 1/metabolismo , Estreptozocina/administração & dosagem , Proteínas Supressoras da Sinalização de Citocina/metabolismo
17.
Nat Commun ; 9(1): 2611, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973593

RESUMO

Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFß signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFß receptor II (TßRII) and are down-regulated in these myeloid cells, leading to increased TßRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFß and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , MicroRNAs/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Animais , Antineoplásicos/farmacologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Interferon gama/genética , Interferon gama/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Transgênicos , MicroRNAs/imunologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Oligorribonucleotídeos/administração & dosagem , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Pirogalol/análogos & derivados , Pirogalol/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Transdução de Sinais , Sulfonamidas/farmacologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
18.
Mol Cell Endocrinol ; 478: 53-61, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30025915

RESUMO

Pituitary corticotroph tumors lead to excess adrenocorticotrophic hormone (ACTH) secretion, resulting in Cushing's disease (CD), which is associated with significant mortality. Standard treatments include neurosurgery, radiotherapy and medical therapy. Both surgery and radiotherapy have undesirable complications and high recurrence rates. At present, there is only one medical option available that targets pituitary adenoma and ACTH secretion, the drug pasireotide. However, hyperglycemia is common during pasireotide treatment. In addition, some patients have discontinued pasireotide treatment because of hyperglycemia-related adverse events or uncontrolled diabetes. New medical treatments directly targeting the corticotroph cells and suppressing ACTH secretion are urgently required. Metformin is a commonly used antidiabetic drug that has been widely used to control the hyperglycemia that occurs in patients with CD, which is secondary to both cortisol excess and pasireotide treatment. Recent studies suggest that metformin has direct anticancer activities against many tumor cell lines. In the present study, we investigated whether metformin exerts an anti-tumor effect by directly targeting pituitary corticotroph tumors and exploring the underlying mechanisms. Using the mouse corticotroph tumor cells, AtT20 cells, we report that metformin inhibited cell proliferation, promoted cell apoptosis and decreased ACTH secretion but did not block the cell cycle in cells. The apoptosis induced by metformin was accompanied by increased caspase-3 activity. Meanwhile, metformin down-regulated the anti-apoptotic protein B cell lymphoma 2 (Bcl-2) but up-regulated the pro-apoptotic protein Bcl2-associated X (BAX), which suggests the involvement of the mitochondrial-mediated apoptosis pathway. Furthermore, metformin promoted AMP-activated protein kinase (AMPK) phosphorylation but inhibited insulin-like growth factor-1 receptor (IGF-1R) expression, protein kinase B (PKB/AKT) phosphorylation and mammalian target of rapamycin (mTOR) phosphorylation. Finally, the IGF-1R inhibitor picropodophyllin (PPP) significantly inhibited the cell proliferation of AtT20 cells. We conclude that metformin inhibits cell proliferation and induces apoptosis in AtT20 cells by activating AMPK/mTOR and inhibiting IGF-1R/AKT/mTOR signaling pathways. Metformin may have direct antitumor activity against pituitary corticotroph tumors.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Corticotrofos/metabolismo , Corticotrofos/patologia , Metformina/farmacologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Adenilato Quinase/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corticotrofos/efeitos dos fármacos , Humanos , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Eur Rev Med Pharmacol Sci ; 22(11): 3515-3523, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29917206

RESUMO

OBJECTIVE: The present study is aimed to investigate the regulatory effect of microRNA (miRNA or miR)-503 on endothelial functions, as well as the mechanism by which high glucose leads to injury of endothelial cells. MATERIALS AND METHODS: When reaching 80% confluency, human umbilical vein endothelial cells (HUVECs) were subjected to non-serum synchronization for 12 h, and medium of cells in high-glucose (HG) group was replaced by normal medium supplemented with 25 mmol/L D-glucose. HUVECs cultured in normal glucose (NG) medium were used as control. To overexpress miR-503, HUVECs were transfected with miR-503 mimics. To silence insulin-like growth factor-1 receptor (IGF-1R) mRNA, HUVECs were transfected with small interfering RNA (siRNA). To predict whether miR-503 targets IGF-1R, bioinformatics was performed. Quantitative Real-time polymerase chain reaction was used to determine miR-503 and IGF-1R mRNA expression, and Western blotting was employed to measure IGF-1R protein expression. Cell-Counting Kit 8 assay was used to determine HUVECs proliferation, while wound-healing assay was used to evaluate HUVECs migration. HUVECs apoptosis was investigated by measuring caspase 3 activity. RESULTS: Expression of IGF-1R in HUVECs in high glucose was decreased compared to that in normal glucose. miR-503 was predicted to target IGF-1R mRNA, and miR-503 expression in HUVECs in high glucose was higher than that in normal glucose. Overexpression of miR-503 inhibited the transcription and the translation of IGF-1R gene reducing migration, suppressed proliferation and promoted apoptosis. Transfection with IGF-1R siRNA decreased IGF-1R protein expression in HUVECs. Down-regulated IGF-1R expression reduced migration and proliferation, but promoted apoptosis of HUVECs. CONCLUSIONS: The present study demonstrates that miR-503 expression in HUVECs is elevated in high glucose condition. Also, miR-503 reduces migration and proliferation, but promotes apoptosis of HUVECs by inhibiting IGF-1R expression.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucose/farmacologia , MicroRNAs/metabolismo , Receptor IGF Tipo 1/metabolismo , Antagomirs/metabolismo , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Regulação para Cima
20.
Oncogene ; 37(40): 5466-5475, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29895971

RESUMO

The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, ß-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response. The ß-catenin/TCF activity high cell lines express components of IGF-1R/IR signaling more than the low cell lines explaining their enhanced sensitivity against IGF-1R/IR TKI. Reinforcing ß-catenin/TCF responsive promoter activity by introducing CTNNB1 gain-of-function mutations into IGF-1R/IR TKI-resistant cells increased the expression and activity of IGF-1R/IR signaling components and also sensitized the cells to IGF-1R/IR TKIs in vitro and in vivo. Analysis of TCGA data revealed that the stronger ß-catenin/TCF responsive promoter activity was associated with higher IGF-1R and IGF2 transcription in human colon cancer specimens as well. Collectively, compared to the mutational status of upstream genes, ß-catenin/TCF responsive promoter activity has potential to be a stronger predictive positive biomarker for IGF-1R/IR TKI responses in colon cancer cells. The present study highlights the potential of transcriptional activity as therapeutic biomarkers for targeted therapies, overcoming the limited ability of upstream genetic mutations to predict responses.


Assuntos
Neoplasias do Colo/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Transcrição Genética/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
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