Abstract
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 3beta. 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.
Highlights
leukotriene D4 (LTD4) is associated with the pathogenesis of several inflammatory disorders, such as asthma and inflammatory bowel disease (IBD) [7]
We have recently shown that the CysLT1 receptor is up-regulated in colon cancer tissue and that LTD4 signaling facilitates the survival of cancer cells [8]
The majority of Wnt-1 in the intestine is believed to come from nonepithelial mesenchymal cells or, intestinal subepithelial myofibroblasts [41], we tested whether LTD4 stimulation could affect the level of Wnt-1 in the human intestinal epithelial cell line Int 407
Summary
LTD4 is associated with the pathogenesis of several inflammatory disorders, such as asthma and inflammatory bowel disease (IBD) [7]. Terized by an increased infiltration of inflammatory leukocytes into the intestinal wall where they have the capacity to cause nonspecific tissue injury These inflammatory cells, in particular the neutrophils, are a significant source of mediators with important regulatory roles in the inflammatory process. -Catenin is a protein with many distinct roles It is found at the cell membrane, where it forms part of the adherens-type junctions, by linking the intracellular domain of the classical type cadherins to the actin cytoskeleton [17, 18]. It was shown that Wnt signaling might be involved in the regulation of cell survival by protecting cells from cytochrome c leakage [29], indirectly suggesting a role for -catenin in this process.
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