Universität zu Köln

Goktuna, Serkan Ismail, Shostak, Kateryna, Chau, Tieu-Lan, Heukamp, Lukas C., Hennuy, Benoit, Ladang, Aurelie, Close, Pierre, Klevernic, Iva, Olivier, Fabrice, Florin, Alexandra, Ehx, Gregory, Baron, Frederic, Vandereyken, Maud ORCID: 0000-0002-6169-7396, Rahmouni, Souad, Vereecke, Lars ORCID: 0000-0002-1593-862X, van Loo, Geert, Buttner, Reinhard, Greten, Florian R. and Chariot, Alain (2016). The Prosurvival IKK-Related Kinase IKK epsilon Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine. Cancer Res., 76 (9). S. 2587 - 2600. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

Full text not available from this repository.

Abstract

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in beta-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikk epsilon to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikk epsilon was also required for lipo-polysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikk epsilon-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikk epsilon phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikk epsilon to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. (C) 2016 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Goktuna, Serkan Ismail UNSPECIFIED UNSPECIFIED UNSPECIFIED Shostak, Kateryna UNSPECIFIED UNSPECIFIED UNSPECIFIED Chau, Tieu-Lan UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennuy, Benoit UNSPECIFIED UNSPECIFIED UNSPECIFIED Ladang, Aurelie UNSPECIFIED UNSPECIFIED UNSPECIFIED Close, Pierre UNSPECIFIED UNSPECIFIED UNSPECIFIED Klevernic, Iva UNSPECIFIED UNSPECIFIED UNSPECIFIED Olivier, Fabrice UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehx, Gregory UNSPECIFIED UNSPECIFIED UNSPECIFIED Baron, Frederic UNSPECIFIED UNSPECIFIED UNSPECIFIED Vandereyken, Maud UNSPECIFIED orcid.org/0000-0002-6169-7396 UNSPECIFIED Rahmouni, Souad UNSPECIFIED UNSPECIFIED UNSPECIFIED Vereecke, Lars UNSPECIFIED orcid.org/0000-0002-1593-862X UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Buttner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Greten, Florian R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chariot, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-276933
DOI:	10.1158/0008-5472.CAN-15-1473
Journal or Publication Title:	Cancer Res.
Volume:	76
Number:	9
Page Range:	S. 2587 - 2600
Date:	2016
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; COLITIS-ASSOCIATED CANCER; CELL-TRANSFORMATION; EPITHELIAL-CELLS; MOLECULE-BETA; BREAST-CANCER; COLON-CANCER; TUMORIGENESIS; INFLAMMATION; PHOSPHORYLATION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27693