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

E Meylan, AL Dooley, DM Feldser, L Shen, E Turk… - Nature, 2009 - nature.com
E Meylan, AL Dooley, DM Feldser, L Shen, E Turk, C Ouyang, T Jacks
Nature, 2009nature.com
NF-κB transcription factors function as crucial regulators of inflammatory and immune
responses as well as of cell survival. They have also been implicated in cellular
transformation and tumorigenesis,,,,. However, despite extensive biochemical
characterization of NF-κB signalling during the past twenty years, the requirement for NF-κB
in tumour development in vivo, particularly in solid tumours, is not completely understood.
Here we show that the NF-κB pathway is required for the development of tumours in a …
Abstract
NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis,,,,. However, despite extensive biochemical characterization of NF-κB signalling during the past twenty years, the requirement for NF-κB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-κB inhibition. Furthermore, the inhibition of NF-κB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-κB signalling in lung tumour 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 Kras and p53.
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