Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Exp Clin Cancer Res ; 39(1): 44, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111229

RESUMO

BACKGROUND: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. METHODS: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. RESULTS: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. CONCLUSIONS: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

2.
BMC Cancer ; 19(1): 706, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319814

RESUMO

BACKGROUND: Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response. METHODS: The effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting. RESULTS: SRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183. CONCLUSIONS: Our data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioblastoma/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Sirtuína 1/metabolismo , Acetilação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/antagonistas & inibidores , Fosforilação , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
3.
Oncol Lett ; 15(1): 515-521, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387232

RESUMO

Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8-activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX). The application of MLN4924 promotes apoptosis and DNA damage in A549/PTX and H460/PTX cells. Additionally, MLN4924 abrogated the 3-dimensional growth potential of these cells and inhibited the formation of the A549/PTX and H460/PTX spheroids. Notably, combining MLN4924 with PTX did not exhibit synergy in PTX-resistant NSCLC cells. Taken together, the results of the current study suggest that MLN4924 may be utilized as an effective strategy for the treatment of PTX-resistant NSCLC.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA