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Fiona Yull

Last active: 3/31/2020

IκB Kinase α Is Required for Development and Progression of -Mutant Lung Adenocarcinoma.

Vreka M, Lilis I, Papageorgopoulou M, Giotopoulou GA, Lianou M, Giopanou I, Kanellakis NI, Spella M, Agalioti T, Armenis V, Goldmann T, Marwitz S, Yull FE, Blackwell TS, Pasparakis M, Marazioti A, Stathopoulos GT
Cancer Res. 2018 78 (11): 2939-2951

PMID: 29588349 · PMCID: PMC6485619 · DOI:10.1158/0008-5472.CAN-17-1944

Although oncogenic activation of NFκB has been identified in various tumors, the NFκB-activating kinases (inhibitor of NFκB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in -mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic Using NFκB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NFκB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of B, IκBβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic -mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage and IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against -mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in -mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease. These findings report a novel requirement for IKKα in mutant lung tumor formation, with potential therapeutic applications. .

©2018 American Association for Cancer Research.

MeSH Terms (16)

A549 Cells Adenocarcinoma of Lung Animals Cell Line Cell Line, Tumor Disease Progression HEK293 Cells Humans I-kappa B Kinase Lung Neoplasms Mice Mice, Inbred C57BL NF-kappa B Protein-Serine-Threonine Kinases Proto-Oncogene Proteins p21(ras) Signal Transduction

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