Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer.
Cell Death Dis
; 15(5): 362, 2024 May 25.
Article
en En
| MEDLINE
| ID: mdl-38796478
ABSTRACT
Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
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Células Madre Neoplásicas
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Factor de Transcripción STAT3
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Quinasas Asociadas a Receptores de Interleucina-1
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Carcinoma Epitelial de Ovario
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Ácido Hialurónico
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos