Journal Article

Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis

Sophia P. Karabela, Ioannis Psallidas, Taylor P. Sherrill, Chrysoula A. Kairi, Rinat Zaynagetdinov, Dong-Sheng Cheng, Spyridoula Vassiliou, Frank McMahon, Linda A. Gleaves, Wei Han, Ioannis Stathopoulos, Spyros G. Zakynthinos, Fiona E. Yull, Charis Roussos, Ioannis Kalomenidis, Timothy S. Blackwell and Georgios T. Stathopoulos

in Carcinogenesis

Volume 33, issue 4, pages 859-867
Published in print April 2012 | ISSN: 0143-3334
Published online January 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs024
Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis

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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.

Journal Article.  6151 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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