| First Author | Göktuna SI | Year | 2016 |
| Journal | Cancer Res | Volume | 76 |
| Issue | 9 | Pages | 2587-99 |
| PubMed ID | 26980769 | Mgi Jnum | J:231832 |
| Mgi Id | MGI:5775235 | Doi | 10.1158/0008-5472.CAN-15-1473 |
| Citation | Goktuna SI, et al. (2016) The Prosurvival IKK-Related Kinase IKKepsilon Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine. Cancer Res 76(9):2587-99 |
| abstractText | 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 Ikkepsilon in Wnt-driven tumor development. We found that Ikkepsilon was activated in intestinal tumors forming upon loss of the tumor suppressor Apc Genetic ablation of Ikkepsilon in beta-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkepsilon to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkepsilon 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 Ikkepsilon-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkepsilon 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 Ikkepsilon to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587-99. (c)2016 AACR. |
