The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine
Author(s)
Date
2016-05Source Title
Cancer Research
Print ISSN
0008-5472
Publisher
American Association for Cancer Research
Volume
76
Issue
9
Pages
2587 - 2599
Language
English
Type
ArticleItem Usage Stats
245
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230
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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.
Keywords
Beta cateninI 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
Permalink
http://hdl.handle.net/11693/37175Published Version (Please cite this version)
https://doi.org/10.1158/0008-5472.CAN-15-1473Collections
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