Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer.
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.
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Allyson G
AG
McLoed
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Taylor P
TP
Sherrill
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Dong-Sheng
DS
Cheng
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Wei
W
Han
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Jamie A
JA
Saxon
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Linda A
LA
Gleaves
Department of Biostatistics, Vanderbilt University, Nashville, TN 37232, USA.
Pingsheng
P
Wu
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Vasiliy V
VV
Polosukhin
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Michael
M
Karin
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave., Nashville, TN 37232, USA.
Fiona E
FE
Yull
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, University of Patras, Rio, 26504 Patras, Greece; Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich 81377, Germany.
Georgios T
GT
Stathopoulos
Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete 71110, Greece.
Vassilis
V
Georgoulias
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: rinat.z.zaynagetdinov@vanderbilt.edu.
Rinat
R
Zaynagetdinov
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave., Nashville, TN 37232, USA; U.S. Department of Veterans Affairs, Washington, DC 20420, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232 USA.
Timothy S
TS
Blackwell
D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis
D053583:Interleukin-1beta; D016328:NF-kappa B; D000069286:Bortezomib; D051550:I-kappa B Kinase