Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma

Abstract

SummaryNF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as cell survival 1 . They have also been implicated in cellular transformation and tumorigenesis [2][3][4][5][6] . However, despite extensive biochemical characterization of NF-κB signaling during the past twenty years, the requirement for NF-κB in tumor development in vivo, particularly in solid tumors, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 and expression of oncogenic K-ras G12D resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing K-ras G12D and lacking p53, p53 restoration led to NF-κB inhibition. Additionally, inhibition of NF-κB signaling induced apoptosis in p53 null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or following tumor progression, resulted in significantly reduced tumor development. Together, these results suggest a critical function for NF-κB signaling in lung tumor development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in K-ras and p53. Keywords NF-κB; lung adenocarcinoma; mouse modelMore than one million people die from lung cancer each year in the world, making it the leading cause of cancer mortality of both women and men. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases, with adenocarcinoma being the major subtype. NSCLC development is associated with frequent mutations in a few well-defined oncogenes and tumor suppressor genes. Oncogenic K-ras mutations occur in approximately 20-30% of

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