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

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Cancer Res ; 81(17): 4417-4430, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233924

RESUMO

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. SIGNIFICANCE: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.


Assuntos
Aciltransferases/metabolismo , Neoplasias Encefálicas/metabolismo , Neuroblastoma/metabolismo , Fosforilação Oxidativa , Animais , Apoptose , Linhagem Celular Tumoral , Colágeno/química , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Concentração Inibidora 50 , Complexo Cetoglutarato Desidrogenase/metabolismo , Laminina/química , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transplante de Neoplasias , Oxigênio/metabolismo , Proteoglicanas/química , Interferência de RNA , Risco , Smegmamorpha , Resultado do Tratamento , Ácidos Tricarboxílicos/metabolismo , Peixe-Zebra
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA