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Arch Biochem Biophys ; 690: 108479, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679194

RESUMO

The upregulation of checkpoint inhibitor PD-L1 expression has recently been associated with nasopharyngeal carcinoma (NPC) resistance to therapy. The mechanism of induction of PD-L1 has also been linked to enhanced aerobic glycolysis promoted by HIF1-α dysregulation and LDH-A activity in cancer. Here, we investigated the effect of the anti-tumoral compound Silibinin on HIF-1α/LDH-A mediated cancer cell metabolism and PD-L1 expression in NPC. Our results demonstrate that exposure to Silibinin potently inhibits tumor growth and promotes a shift from aerobic glycolysis toward oxidative phosphorylation. The EBV + NPC cell line C666-1 and glycolytic human tumor explants treated with Silibinin displayed a reduction in LDH-A activity which consistently associated with a reduction in lactate levels. This effect was accompanied by an increase in intracellular citrate levels in C666-1 cells. Accordingly, expression of HIF-1α, a critical regulator of glycolysis, was down-regulated after treatment. This event associated with a down-regulation in PD-L1. Altogether, our results provide evidence that silibinin can alter PD-L1 expression by interfering with HIF-1α/LDH-A mediated cell metabolism in NPC. These results provide a new perspective for Silibinin use to overcome PD-L1 mediated NPC resistance to therapy.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Antígeno B7-H1/genética , Glicólise/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Silibina/metabolismo , Adolescente , Adulto , Antineoplásicos Fitogênicos/farmacologia , Antígeno B7-H1/metabolismo , Biópsia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico , Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactato Desidrogenase 5/metabolismo , Pessoa de Meia-Idade , Fosforilação Oxidativa , Transdução de Sinais , Silibina/farmacologia
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