The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma.
Cancer Res
; 82(24): 4555-4570, 2022 12 16.
Article
em En
| MEDLINE
| ID: mdl-36214632
ABSTRACT
Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression. SIGNIFICANCE:
The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas ras
/
Inibidores de Proteínas Quinases
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RNA Longo não Codificante
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Melanoma
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article