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1.
Cell Death Dis ; 11(12): 1035, 2020 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-33279931

RESUMO

Medulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.


Assuntos
Comunicação Autócrina , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Interleucina-6/metabolismo , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Receptores de Interleucina-6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vincristina/farmacologia , Vincristina/uso terapêutico
2.
J Mol Diagn ; 21(4): 705-717, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31055024

RESUMO

Formalin fixation is the standard method for the preservation of tissue for diagnostic purposes, including pathologic review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic test results. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade, laboratory-developed targeted resequencing assay. Several parameters relating to sequencing quality and variant calling were examined and quantified in tumor and normal colon epithelial tissues. We identified an alternative fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathologic review.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Fixação de Tecidos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Imuno-Histoquímica , Inclusão em Parafina , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas
3.
Mol Cell Biol ; 33(21): 4334-45, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24001772

RESUMO

Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging α4ß1-integrin or α5ß1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of α4δ, a truncated α4-integrin with KXGFFKR as the cytoplasmic motif, in α4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of α4-mediated adhesion. The adhesion-independent chemoresistance did not require ß1-integrin as the heterodimeric pair, since expression of Tacδ, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing α4δ and Tacδ. Cells expressing α4δ and Tacδ exhibited a high influx of extracellular Ca(2+), and inhibition of Ca(2+) channels with verapamil attenuated the adhesion-independent chemoresistance. Tacδ cells also exhibited greater rates of drug efflux. α4δ and Tacδ interacted with the Ca(2+)-binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of α4-integrins promoted an increased calreticulin-α4 association and greater influx of extracellular Ca(2+) than in nonadherent cells. The α-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Integrina alfa4/metabolismo , Sequência de Aminoácidos , Antibióticos Antineoplásicos/metabolismo , Apoptose , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio , Calreticulina/metabolismo , Adesão Celular , Sobrevivência Celular , Doxorrubicina/metabolismo , Humanos , Integrina alfa4/química , Integrina alfa5/metabolismo , Integrina beta1/metabolismo , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Células Jurkat , Dados de Sequência Molecular , Fragmentos de Peptídeos/biossíntese , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo
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