The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine
Göktuna, S. I.
Loo, G. V.
Greten, F. R.
American Association for Cancer Research
2587 - 2599
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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.
I kappa B kinase epsilon
Immunoglobulin enhancer binding protein
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
I kappa B kinase
Intestine epithelium cell
Tumor associated leukocyte
In situ hybridization
Real time polymerase chain reaction
Tumor cell line
Cell Line, Tumor
Disease Models, Animal
I-kappa B Kinase
In Situ Hybridization
Real-Time Polymerase Chain Reaction
Published Version (Please cite this version)https://doi.org/10.1158/0008-5472.CAN-15-1473
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