Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFκB Activation
Kelly Flentie1, Caleb Gonzalez2, Brandon Kocher1
1Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
Molecular Cancer Research : MCR
|March 11, 2018
Summary
Bacterial flagellin activates toll-like receptor 5 (TLR5) signaling, enhancing antitumor immunity. Nucleoside diphosphate kinase 3 (NME3) was identified as a key regulator, improving survival in several cancers.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Bacterial flagellin activates innate immunity via toll-like receptor 5 (TLR5) and NFκB signaling.
- Flagellin shows potential as an antitumor ligand, promoting host immunity against tumors.
Purpose of the Study:
- To identify innate signaling components of TLR5 crucial for its antitumor effects.
- To uncover novel tumor cell modulators of TLR5-induced NFκB activation.
Main Methods:
- A high-throughput loss-of-function screen using siRNA targeting human kinases.
- Carcinoma cells with a bioluminescent NFκB reporter stimulated by flagellin-expressing *Salmonella typhimurium*.
- Knockdown and overexpression assays to validate candidate regulators.
Main Results:
- Nucleoside diphosphate kinase 3 (NME3) was identified as a positive regulator of TLR5-mediated NFκB signaling, acting downstream of MyD88.
- NME3 expression correlated with TLR5 expression across multiple cancer types.
- High NME3 levels improved survival in breast, lung, and ovarian cancers, but decreased survival in gastric cancer.
Conclusions:
- NME3 plays a proinflammatory role downstream of TLR5, enhancing signaling responses to flagellin.
- NME3's modulation of TLR5 signaling may potentiate cancer immunotherapies and impact patient survival differently across cancer types.
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