The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine

Date
2016-05
Authors
Göktuna, S. I.
Shostak, K.
Chau, T.-L.
Heukamp, L.C.
Hennuy, B.
Duong, H.-Q.
Ladang, A.
Close, P.
Klevernic, I.
Olivier, F.
Advisor
Supervisor
Co-Advisor
Co-Supervisor
Instructor
Source Title
Cancer Research
Print ISSN
0008-5472
Electronic ISSN
Publisher
American Association for Cancer Research
Volume
76
Issue
9
Pages
2587 - 2599
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
Series
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 b-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 proinflammatory 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.

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Book Title
Keywords
Beta catenin, I kappa B kinase epsilon, Immunoglobulin enhancer binding protein, Interleukin 17, Lipopolysaccharide, Mitogen activated protein kinase 1, Mitogen activated protein kinase 3, Mitogen activated protein kinase kinase 1, Mitogen activated protein kinase kinase 2, Protein kinase B, Stress activated protein kinase 1, Wnt protein, I kappa B kinase, Interleukin 17, Lipopolysaccharide, Wnt protein, Animal cell, Animal experiment, Animal model, Animal tissue, Apoptosis, Article, Cancer growth, Cancer incidence, Cancer survival, Controlled study, Intestine cancer, Intestine epithelium cell, Mouse, Nonhuman, Positive feedback, Priority journal, Protein expression, Protein function, Protein phosphorylation, Signal transduction, Tumor associated leukocyte, Tumor microenvironment, Tumor promotion, Animal, Disease model, Flow cytometry, Human, Immunoprecipitation, In situ hybridization, Intestine tumor, Metabolism, Pathology, Physiology, Real time polymerase chain reaction, Transgenic mouse, Tumor cell line, Animals, Cell Line, Tumor, Disease Models, Animal, Flow Cytometry, Humans, I-kappa B Kinase, Immunoprecipitation, In Situ Hybridization, Interleukin-17, Intestinal Neoplasms, Lipopolysaccharides, Mice, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Signal Transduction, Tumor Microenvironment, Wnt Proteins
Citation
Published Version (Please cite this version)