1. Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer.
- Author
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Standing D, Dandawate P, Gunewardena S, Covarrubias-Zambrano O, Roby KF, Khabele D, Jewell A, Tawfik O, Bossmann SH, Godwin AK, Weir SJ, Jensen RA, and Anant S
- Subjects
- Humans, Female, Animals, Cell Line, Tumor, Mice, Cisplatin pharmacology, Mice, Nude, Phosphorylation drug effects, Cell Proliferation drug effects, Molecular Weight, Xenograft Model Antitumor Assays, Interleukin-1 Receptor-Associated Kinases metabolism, Interleukin-1 Receptor-Associated Kinases antagonists & inhibitors, STAT3 Transcription Factor metabolism, Carcinoma, Ovarian Epithelial metabolism, Carcinoma, Ovarian Epithelial pathology, Carcinoma, Ovarian Epithelial drug therapy, Carcinoma, Ovarian Epithelial genetics, Hyaluronic Acid metabolism, Hyaluronic Acid pharmacology, Ovarian Neoplasms pathology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism, Ovarian Neoplasms genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology
- 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., (© 2024. The Author(s).)
- Published
- 2024
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