Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Vreka, Malamati UNSPECIFIED UNSPECIFIED UNSPECIFIED Lilis, Ioannis UNSPECIFIED UNSPECIFIED UNSPECIFIED Papageorgopoulou, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Giotopoulou, Georgia A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lianou, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Giopanou, Ioanna UNSPECIFIED orcid.org/0000-0003-4393-7517 UNSPECIFIED Kanellakis, Nikolaos I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spella, Magda UNSPECIFIED UNSPECIFIED UNSPECIFIED Agalioti, Theodora UNSPECIFIED orcid.org/0000-0002-5898-2751 UNSPECIFIED Armenis, Vasileios UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldmann, Torsten UNSPECIFIED orcid.org/0000-0002-1621-560X UNSPECIFIED Marwitz, Sebastian UNSPECIFIED orcid.org/0000-0003-4920-5552 UNSPECIFIED Yull, Fiona E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Blackwell, Timothy S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Marazioti, Antonia UNSPECIFIED UNSPECIFIED UNSPECIFIED Stathopoulos, Georgios T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language MOUSE MODELS; CELL-PROLIFERATION; GENE-EXPRESSION; IKK-ALPHA; CANCER; ACTIVATION; INHIBITION; BETA; RAS; CARCINOGENESIS Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18470