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

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

来源：Carcinogenesis, 2012, 33(4): 859-867.

DOI：10.1093/carcin/bgs024

Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-kappa B signaling in lung tumorigenesis, we investigated the impact of the NF-kappa B inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-kappa B 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-kappa B 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-1 beta and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-kappa B 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-1 beta, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-kappa B inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-kappa B in pulmonary macrophages appears to play an important role in this adverse process.

• 出版日期2012-4