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1.
Theranostics ; 10(4): 1833-1848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042339

RESUMO

Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

2.
J Biol Chem ; 294(25): 10006-10017, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31101655

RESUMO

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

3.
Cancer Lett ; 418: 64-74, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29331413

RESUMO

The roles of microRNA in regulation of various biological processes and in modulation of therapeutic effects have been widely appreciated. In this study, we found a positive correlation between miR-449 b expression and radiation sensitivity in cancer cells and in tumor specimens from patients. We showed that eEF-2 kinase, a negative regulator of global protein synthesis, is a target of miR-449 b. Introducing a miR-449 b mimic into cancer cells led to suppression of eEF-2 kinase expression, leading to increases of protein synthesis and depletion of cellular ATP. Further, we demonstrated that the miR-449 b mimic rendered the cancer cells more sensitive to ionizing radiation both in vitro (cell culture) and in vivo (animal xenograft model). Moreover, the radiation sensitivity conferred by miR-449 b could be blunted by cycloheximide, an inhibitor of protein synthesis, or by direct delivery of ATP liposome, supporting eEF-2 kinase as a mediator of the radio-sensitizing effects of miR-449 b. These results indicate that miR-449 b, which is frequently down-regulated in radio-resistant cancers, may represent a new critical determinant of radio-sensitivity.


Assuntos
Quinase do Fator 2 de Elongação/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Neoplasias/radioterapia , Tolerância a Radiação/genética , Regiões 3' não Traduzidas/genética , Células A549 , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Quinase do Fator 2 de Elongação/metabolismo , Feminino , Células HeLa , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nutr Cancer ; 65(6): 891-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23909734

RESUMO

In this study we demonstrated that Triticuside A, one of the flavonoid compounds isolated from wheat bran, induced apoptosis and inhibited proliferation of human breast cancer cells. Triticuside A inhibited the proliferation of human breast cancer cells (MCF-7 and MDA-MB-231) in a dose-dependent manner but barely showed cytotoxicity to the normal human fibroblasts. Triticuside A-induced apoptosis was accompanied by a significant decrease of Mcl-1 and Bcl-2 proteins and by an increase of cleavage of caspases-3, -7, -9, and PARP. Triticuside A also suppressed the level of phospho-Akt and its downstream targets, mTOR and P70 S6 kinase. LY294002, a specific inhibitor of PI3K, significantly enhanced the Triticuside A-induced apoptosis. Moreover LY294002 not only downregulated the level of phospho-Akt but also enhanced the inhibition of Mcl-1 expression when combined with Triticuside A. Our results demonstrate for the first time the specific apoptogenic activity of Triticuside A in tumor cells and involvement of the mitochondrial apoptosis pathway and Akt/mTOR signaling pathway. Thus, Triticuside A may be a potentially useful wheat bran component that can be used for prevention or treatment of breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Glicosídeos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Cromonas/farmacologia , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Células MCF-7 , Morfolinas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Genetics ; 189(3): 899-906, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21868605

RESUMO

Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6- or SLT-1-induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues.


Assuntos
Acetilcolina/metabolismo , Axônios/metabolismo , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Sinais (Psicologia) , Acetilcolina/farmacologia , Animais , Axônios/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Cones de Crescimento/efeitos dos fármacos , Cones de Crescimento/metabolismo , Movimento/efeitos dos fármacos , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Netrinas , Receptores Nicotínicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
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