Τίτλος:
Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1β and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1β, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process. © The Author 2012. Published by Oxford University Press. All rights reserved.
Συγγραφείς:
Karabela, S.P.
Psallidas, I.
Sherrill, T.P.
Kairi, C.A.
Zaynagetdinov, R.
Cheng, D.-S.
Vassiliou, S.
Mcmahon, F.
Gleaves, L.A.
Han, W.
Stathopoulos, I.
Zakynthinos, S.G.
Yull, F.E.
Roussos, C.
Kalomenidis, I.
Blackwell, T.S.
Stathopoulos, G.T.
Περιοδικό:
Journal of Carcinogenesis
Εκδότης:
Oxford University Press
Λέξεις-κλειδιά:
bortezomib; CXCL1 chemokine; CXCL2 chemokine; I kappa B; interleukin 1beta; interleukin 6; urethan, animal cell; animal experiment; animal model; apoptosis; article; cancer inhibition; carcinogenesis; cell survival; controlled study; down regulation; drug effect; enzyme activation; enzyme inhibition; histology; immunoreactivity; in vivo study; lung adenocarcinoma; lung alveolus epithelium; lung alveolus macrophage; lung carcinogenesis; lung lavage; lung tumor; mouse; nonhuman; phenotype; pneumonia; priority journal; protein expression; protein motif; treatment duration; tumor growth; tumor promotion; tumor volume; upregulation
DOI:
10.1093/carcin/bgs024
