NF-kappaB 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-kappaB signalling during the past twenty years, the requirement for
NF-kappaB in
tumour development in vivo, particularly in
solid tumours, is not completely understood. Here we show that the
NF-kappaB 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-kappaB activation in primary
mouse embryonic fibroblasts. Conversely, in
lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration
led to
NF-kappaB inhibition. Furthermore, the inhibition of
NF-kappaB 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-kappaB signalling in
lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of
NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined
mutations in Kras and p53.
