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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-05, Vol.76 (9), p.2587-2599
• Main Authors: Göktuna, Serkan Ismail, Shostak, Kateryna, Chau, Tieu-Lan, Heukamp, Lukas C, Hennuy, Benoit, Duong, Hong-Quan, Ladang, Aurélie, Close, Pierre, Klevernic, Iva, Olivier, Fabrice, Florin, Alexandra, Ehx, Grégory, Baron, Frédéric, Vandereyken, Maud, Rahmouni, Souad, Vereecke, Lars, van Loo, Geert, Büttner, Reinhard, Greten, Florian R, Chariot, Alain
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Disease Models, Animal; Flow Cytometry; Humans; I-kappa B Kinase - metabolism; Immunoprecipitation; In Situ Hybridization; Interleukin-17 - metabolism; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Lipopolysaccharides - metabolism; Mice; Mice, Transgenic; Real-Time Polymerase Chain Reaction; Signal Transduction - physiology; Tumor Microenvironment - physiology; Wnt Proteins - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-1473

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. ©2016 AACR.