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Cancer Res. 2016 May 1;76(9):2587-99. doi: 10.1158/0008-5472.CAN-15-1473. Epub 2016 Mar 15.

The Prosurvival IKK-Related Kinase IKKε Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine.

Author information

1
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium. Department of Molecular Biology and Genetics, Bilkent University, Bilkent, Ankara, Turkey.
2
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
3
Institute for Pathology-University Hospital Cologne, Germany.
4
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. GIGA Transcriptomic Facility, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
5
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Cancer Signaling, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
6
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Animal Facility, Liège, University of Liege, Belgium.
7
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Hematology and Department of Medicine, Division of Hematology, GIGA-I, University of Liege, Liège, Belgium.
8
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Immunology and Infectious Diseases, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
9
Inflammation Research Centre (IRC), VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
10
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
11
Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), University of Liege, Liège, Belgium. alain.chariot@ulg.ac.be.

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 Ikkε in Wnt-driven tumor development. We found that Ikkε was activated in intestinal tumors forming upon loss of the tumor suppressor Apc Genetic ablation of Ikkε in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkε to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkε was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkε-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkε 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 Ikkε to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587-99.

PMID:
26980769
DOI:
10.1158/0008-5472.CAN-15-1473
[Indexed for MEDLINE]
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