Vreka, Malamati, Lilis, Ioannis, Papageorgopoulou, Maria, Giotopoulou, Georgia A., Lianou, Marina, Giopanou, Ioanna ORCID: 0000-0003-4393-7517, Kanellakis, Nikolaos I., Spella, Magda, Agalioti, Theodora ORCID: 0000-0002-5898-2751, Armenis, Vasileios, Goldmann, Torsten ORCID: 0000-0002-1621-560X, Marwitz, Sebastian ORCID: 0000-0003-4920-5552, Yull, Fiona E., Blackwell, Timothy S., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Marazioti, Antonia and Stathopoulos, Georgios T. (2018). I kappa B Kinase alpha Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma. Cancer Res., 78 (11). S. 2939 - 2952. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Although oncogenic activation of NF kappa B has been identified in various tumors, the NF kappa B-activating kinases (inhibitor of NF kappa B kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKK alpha and IKK beta in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NF kappa B reporter mice and conditional deletions of IKK alpha and IKK beta, we identified two distinct early and late activation phases of NF kappa B during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, I kappa B beta, and IKK alpha in tumor-initiated cells. IKK alpha was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKK alpha-deficient mice were markedly protected from the disease. IKK alpha specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKK alpha was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKK beta inhibitor. These results demonstrate an actionable requirement for IKK alpha in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease. Significance: These findings report a novel requirement for IKK alpha in mutant KRAS lung tumor formation, with potential therapeutic applications. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Vreka, MalamatiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lilis, IoannisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papageorgopoulou, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giotopoulou, Georgia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lianou, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giopanou, IoannaUNSPECIFIEDorcid.org/0000-0003-4393-7517UNSPECIFIED
Kanellakis, Nikolaos I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spella, MagdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agalioti, TheodoraUNSPECIFIEDorcid.org/0000-0002-5898-2751UNSPECIFIED
Armenis, VasileiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldmann, TorstenUNSPECIFIEDorcid.org/0000-0002-1621-560XUNSPECIFIED
Marwitz, SebastianUNSPECIFIEDorcid.org/0000-0003-4920-5552UNSPECIFIED
Yull, Fiona E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blackwell, Timothy S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Marazioti, AntoniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stathopoulos, Georgios T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-184701
DOI: 10.1158/0008-5472.CAN-17-1944
Journal or Publication Title: Cancer Res.
Volume: 78
Number: 11
Page Range: S. 2939 - 2952
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOUSE MODELS; CELL-PROLIFERATION; GENE-EXPRESSION; IKK-ALPHA; CANCER; ACTIVATION; INHIBITION; BETA; RAS; CARCINOGENESISMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18470

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