Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL-18 mediated inflammation-independent mechanism

Deswaerte, V; Nguyen, PM; West, A; Browning, AF; Yu, L; Ruwanpura, S; Balic, J; Livis, T; Girard, C; Preaudet, A; Oshima, H; Fung, KY; Tye, H; Najdovska, M; Ernst, M; Oshima, M; Gabay, C; Putoczki, TL; Jenkins, BJ

Author(s): Deswaerte, V; Nguyen, PM; West, A; Browning, AF; Yu, L; Ruwanpura, S; Balic, J; Livis, T; Girard, C; Preaudet, A; Oshima, H; Fung, KY; Tye, H; Najdovska, M; Ernst, M; Oshima, M; Gabay, C; Putoczki, TL; Jenkins, BJ;
Details: Publication Year 2018,Volume 78,Issue #5,Page 1293-1307
Journal Title: Cancer Research
Publication Type: Journal Article
Abstract: Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a pro-tumorigenic role in gastric cancer (GC) for the key inflammasome adaptor ASC and its effector cytokine IL-18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type GC suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-kappaB activation and reduced expression of mature IL-18, but not IL-1beta, in gastric tumors. Genetic ablation of IL-18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL-1beta and IL-1alpha activity upon genetic ablation of the IL-1 receptor had no effect. The specific pro-tumorigenic role for IL-18 was associated with high IL-18 gene expression in the gastric tumor epithelium compared to IL-1beta, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL-18, we found it to be highly secreted from human GC cell lines. Moreover, IL-18 blockade either by a neutralizing anti-IL-18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human GC cells. In clinical specimens of human GC tumors, we observed a significant positive correlation between elevated mature IL-18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL-18 signaling axis as a candidate therapeutic target in GC.
Publisher: AACR
Research Division(s): Inflammation
PubMed ID: 29282220
Publisher's Version: https://doi.org/10.1158/0008-5472.CAN-17-1887
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-01-15 12:39:50

Last Modified: 2018-05-04 12:11:20