Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer.
Interleukin-1 Receptor-Associated Kinases
/ metabolism
Humans
STAT3 Transcription Factor
/ metabolism
Female
Carcinoma, Ovarian Epithelial
/ metabolism
Hyaluronic Acid
/ metabolism
Animals
Ovarian Neoplasms
/ pathology
Neoplastic Stem Cells
/ metabolism
Cell Line, Tumor
Mice
Cisplatin
/ pharmacology
Mice, Nude
Phosphorylation
/ drug effects
Cell Proliferation
/ drug effects
Molecular Weight
Xenograft Model Antitumor Assays
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 May 2024
25 May 2024
Historique:
received:
29
11
2023
accepted:
02
05
2024
revised:
30
04
2024
medline:
26
5
2024
pubmed:
26
5
2024
entrez:
25
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38796478
doi: 10.1038/s41419-024-06717-3
pii: 10.1038/s41419-024-06717-3
doi:
Substances chimiques
Interleukin-1 Receptor-Associated Kinases
EC 2.7.11.1
STAT3 Transcription Factor
0
Hyaluronic Acid
9004-61-9
IRAK1 protein, human
EC 2.7.11.1
STAT3 protein, human
0
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
362Subventions
Organisme : NCI NIH HHS
ID : P30 CA168524
Pays : United States
Organisme : Kansas University | University of Kansas Medical Center (KUMC)
ID : None
Informations de copyright
© 2024. The Author(s).
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