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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Malignant Pleural Effusion; Ikk-beta; Mouse Model; Activation; Carcinogenesis; Tumorigenesis; Inflammation; Cells; Adenocarcinoma; Proliferation
Sprache englisch
Veröffentlichungsjahr 2016
HGF-Berichtsjahr 2016
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 16, Heft: 1, Seiten: 120-132 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Lung Research
PSP-Element(e) 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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