p38γ MAPK is required for inflammation-associated colon tumorigenesis

Chronic inflammation has long been considered to causatively link to colon cancer development. However, signal transduction pathways involved remain largely unidentified. Here, we report that p38 gamma mitogen-activated protein kinase mediates inflammatory signaling to promote colon tumorigenesis. Inflammation activates p38 gamma in mouse colon tissues and intestinal epithelial cell-specific p38 gamma knockout (KO) attenuates colitis and inhibits pro-inflammatory cytokine expression. Significantly, p38 gamma KO inhibits tumorigenesis in a colitis-associated mouse model. The specific p38 gamma pharmacological inhibitor pirfenidone also suppresses pro-inflammatory cytokine expression and colon tumorigenesis. The tumor-promoting activity of epithelial p38 gamma was further demonstrated by xenograft studies. In addition, p38 gamma is required for beta-catenin/Wnt activities and p38 gamma stimulates Wnt transcription by phosphorylating beta-catenin at Ser605. These results show that p38 gamma activation links inflammation and colon tumorigenesis. Targeting p38 gamma may be a novel strategy for colon cancer prevention and treatment.