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

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 Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke 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 Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke 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 Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9);

The role of microbiota in the development of colorectal cancer

“…IL‐17 is produced by a subpopulation of Th17 cells . The IL‐17‐dependent signaling pathway promotes NF‐κB and Wnt activation, and establishes an inflammatory tumor microenvironment in the gut . Furthermore, administration of an IL‐17‐blocking antibody had an inhibitory effect on excess tumor formation, indicating that IL‐17 is necessary for tumorigenesis in this model .…”

The role of interleukin-17 in tumor development and progression

“…The close proximity of IL-17R and EGFR allows the adaptor protein Act1 to recruit c-Src for IL-17A-induced EGFR transactivation, enabling the activation of the MEK3-MEK5-ERK5 axis. Additionally, a substantial body of literature indicates that IL-17 stimulation is able to directly promote cell proliferation (e.g., keratinocytes and intestinal epithelial cells) by activating mitogenic signaling pathways such as ERK1/2 (Göktuna et al, 2016;Ha et al, 2014;Qian et al, 2007;Shen et al, 2009;Song et al, 2015;Wang et al, 2014;Zepp et al, 2017). Notably, ERK1/2 and ERK5 were shown to regulate distinct sets of genes (Schweppe et al, 2006).…”

IKKs and tumor cell plasticity

“…MAPKs are required for c-Myc stabilization upon activation of toll-like receptor signaling in Wnt-driven tumor models [75]. Hence, MAPKs and their downstream transcription factors regulate the expression of various cytokines and proliferative factors by co-operating with NF-jB at promoter regions of target genes [74,76]. However, in later studies, our colleagues have proven that this proinflammatory environment created by constitutive IKKb activation is not only required for tumor initiation and progression but also for invasion and metastasis upon p53 loss [77].…”