title: Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis.
abstract: 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.
authors.affiliation: Applied Biomedical Research and Training Center Marianthi Simou, Department of Critical Care and Pulmonary Services, General Hospital Evangelismos, School of Medicine, National and Kapodistrian University of Athens, 10675 Athens, Greece.
authors.forename: Sophia P
authors.initials: SP
authors.lastname: Karabela
authors.forename: Ioannis
authors.initials: I
authors.lastname: Psallidas
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.forename: Chrysoula A
authors.initials: CA
authors.lastname: Kairi
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Spyridoula
authors.initials: S
authors.lastname: Vassiliou
authors.forename: Frank
authors.initials: F
authors.lastname: McMahon
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stathopoulos
authors.forename: Spyros G
authors.initials: SG
authors.lastname: Zakynthinos
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kalomenidis
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Georgios T
authors.initials: GT
authors.lastname: Stathopoulos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib