Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer.

Abstract

Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis, and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors.

• Authors: Allyson G McLoed, Taylor P Sherrill, Dong-Sheng Cheng, Wei Han, Jamie A Saxon, Linda A Gleaves, Pingsheng Wu, Vasiliy V Polosukhin, Michael Karin, Fiona E Yull, Georgios T Stathopoulos, Vassilis Georgoulias, Rinat Zaynagetdinov, Timothy S Blackwell
• Journal: Cell reports (Cell Rep) Vol. 16 Issue 1 Pg. 120-132 (06 28 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27320908 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-1beta
• NF-kappa B
• Bortezomib
• I-kappa B Kinase

Topics

• Animals
• Bortezomib (pharmacology, therapeutic use)
• Carcinogenesis (drug effects, pathology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Epithelial Cells (metabolism, pathology)
• Humans
• I-kappa B Kinase (metabolism)
• Interleukin-1beta (metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Myeloid Cells (drug effects, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neutrophils (drug effects, metabolism)
• Signal Transduction (drug effects)
• Survival Analysis