IL-33-dependent NF-κB activation inhibits apoptosis and drives chemoresistance in acute myeloid leukemia.
Cytokine
; 180: 156672, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38852492
ABSTRACT
BACKGROUND:
Despite recent advances in therapeutic regimens, the prognosis of acute myeloid leukemia (AML) remains poor. Following our previous finding that interleukin-33 (IL-33) promotes cell survival along with activated NF-κB in AML, we further investigated the role of NF-κB during leukemia development.METHODS:
Flow cytometry was performed to value the apoptosis and proliferation. qRT-PCR and western blot were performed to detect the expression of IL-6, active caspase 3, BIRC2, Bcl-2, and Bax, as well as activated NF-κB p65 and AKT. Finally, xenograft mouse models and AML patient samples were used to verify the findings observed in AML cell lines.RESULTS:
IL-33-mediated NF-κB activation in AML cell lines contributes to a reduction in apoptosis, an increase in proliferation rate as well as a decrease in drug sensitivity, which were reversed by NF-κB inhibitor, Bay-117085. Moreover, IL-33 decreased the expression of active caspase-3 while increasing the levels of BIRC2, Bcl-2, and Bax, and these effects were blocked by Bay-117085. Additionally, NF-κB activation induced by IL-33 increases the production of IL-6 and autocrine activation of AKT. Co-culture of bone marrow stroma with AML cells resulted in increased IL-33 expression by leukemia cells, along with decreased apoptosis level and reduced drug sensitivity. Finally, we confirmed the in vivo pro-tumor effect mediated by IL-33/ NF-κB axis using a xenograft model of AML.CONCLUSION:
Our data indicate that IL-33/IL1RL1-dependent signaling contributes to AML cell activation of NF-κB, which in turn causes autocrine IL-6-induced activation of pAKT, supporting IL-33/NF-κB/pAKT as a potential target for AML therapy.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
NF-kappa B
/
Apoptose
/
Resistencia a Medicamentos Antineoplásicos
/
Interleucina-33
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article