Inflammatory Mediator Leukotriene D₄ Induces [beta]-Catenin Signaling and Its Association with Antiapoptotic Bcl-2 in Intestinal Epithelial Cells

• Published in: The Journal of biological chemistry 2006, Vol.281 (10), p.6776-6784
• Main Authors: Mezhybovska, Maryna, Wikström, Katarina, Öhd, John F, Sjölander, Anita
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X

Increased levels of the inflammatory mediator leukotriene D₄ (LTD₄) are present at sites of inflammatory bowel disease, and such areas also exhibit an increased risk for subsequent cancer development. It is known that LTD₄ affects the expression of many proteins that influence survival and proliferation of intestinal epithelial cells. We demonstrate here that after LTD₄ exposure, [beta]-catenin translocates to the nucleus where it signals activation of the TCF/LEF family of transcription factors. These events are mediated via a phosphatidylinositol 3-kinase-dependent phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase 3[beta]. We also show that in the presence of LTD₄, free [beta]-catenin translocates to the mitochondria where it associates with the cell survival protein Bcl-2. We hypothesize that LTD₄ may enhance cell survival via activation of [beta]-catenin signaling, in particular, by promoting the association of [beta]-catenin with Bcl-2 in the mitochondria. Similar to Wnt-1 signaling, LTD₄ signals an increased level of free [beta]-catenin and elevated TCF/LEF promotor activity. This work in intestinal epithelial cells further lends credence to the idea that inflammatory signaling pathways are intrinsically linked with potential oncogenic signals involved in cell survival and apoptosis.