Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.
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.
Koch Institute for Integrative Cancer Research, and Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Etienne
E
Meylan
Alison L
AL
Dooley
David M
DM
Feldser
Lynn
L
Shen
Erin
E
Turk
Chensi
C
Ouyang
Tyler
T
Jacks
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D004247:DNA; D015689:Oncogene Protein p21(ras)