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McLoed, A.G.* ; Sherrill, T.P.* ; Cheng, D.S.* ; Han, W.* ; Saxon, J.A.* ; Gleaves, L.A.* ; Wu, P.* ; Polosukhin, V.V.* ; Karin, M.* ; Yull, F.E.* ; Stathopoulos, G.T. ; Georgoulias, V.* ; Zaynagetdinov, R.* ; Blackwell, T.S.*

Neutrophil-derived IL-1β impairs the efficacy of NF-κB inhibitors against lung cancer.

Cell Rep. 16, 120-132 (2016)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Malignant Pleural Effusion; Ikk-beta; Mouse Model; Activation; Carcinogenesis; Tumorigenesis; Inflammation; Cells; Adenocarcinoma; Proliferation
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 16, Issue: 1, Pages: 120-132 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501600-003
PubMed ID 27320908
DOI 10.1016/j.celrep.2016.05.085
WOS ID WOS:000378950700012
Erfassungsdatum 2016-06-27
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