Non-apoptotic function of caspase-8 confers prostate cancer enzalutamide resistance via NF-κB activation.
Cell Death Dis
; 12(9): 833, 2021 09 04.
Article
em En
| MEDLINE
| ID: mdl-34482382
ABSTRACT
Caspase-8 is a unique member of caspases with a dual role in cell death and survival. Caspase-8 expression is often lost in some tumors, but increased in others, indicating a potential pro-survival function in cancer. By analyzing transcriptome of enzalutamide-resistant prostate cancer cells, we found that resistance was conferred by a mild caspase-8 upregulation that in turn led to NF-κB activation and the subsequent upregulation of the downstream IL-8. Mechanistically, we found that the pro-survival and enzalutamide-resistance-promoting features of caspase-8 were independent of its proteolytic activity, using a catalytically-inactive caspase-8 mutant. We further demonstrated that caspase-8 pro-apoptotic function was inhibited via cFLIP binding. Moreover, high caspase-8 expression was correlated with a worse prognosis in prostate cancer patients. Collectively, our work demonstrates that enzalutamide-resistance is mediated by caspase-8 upregulation and the consequent increase in NF-κB/IL-8 mediated survival signaling, highlighting caspase-8 and NF-κB as potential therapeutic targets to overcome enzalutamide-resistance in CRPC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Feniltioidantoína
/
Neoplasias da Próstata
/
Benzamidas
/
NF-kappa B
/
Apoptose
/
Resistencia a Medicamentos Antineoplásicos
/
Caspase 8
/
Nitrilas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2021
Tipo de documento:
Article