Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics.
Cancer Cell
; 29(2): 145-58, 2016 Feb 08.
Article
en En
| MEDLINE
| ID: mdl-26859455
Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia
/
Proteínas Serina-Treonina Quinasas
/
Imitación Molecular
/
Proteínas Mitocondriales
/
Proteínas Quinasas p38 Activadas por Mitógenos
/
Péptidos y Proteínas de Señalización Intracelular
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2016
Tipo del documento:
Article
País de afiliación:
Australia