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
Item Usage Stats
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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