LTD4 signalling via beta-catenin: a possible link between inflammation and cancer

Sammanfattning: The pro-inflammatory mediator LTD4 is an important component in the pathogenesis of inflammatory conditions as inflammatory bowel diseases. Patients suffering from inflammatory bowel diseases face an increased risk of intestinal cancer development. Therefore it is important to investigate the role of LTD4 signalling in cancer development and progression. In this thesis I show that there is an endogenous production of LTD4 in both non-transformed and cancer intestinal epithelial cells leading to a continuous activation of the CysLT1 receptor. The activation of this receptor signals increased proliferation and increased survival. My finding that CysLT1 receptor signalling leads to accumulation of b-catenin in the nuclei and activation of the transcription factor TCF/LEF is in line with the ability of this receptor to promote cell proliferation. However, I also found that CysLT1 receptor activation caused b-catenin to translocate to the mitochondria where it associated with the survival protein Bcl-2. In addition, I observed that LTD4-induced activation of the CysLT1 receptor or overexpression of b-catenin in both non-transformed and cancer intestinal epithelial cells enhanced the activity of the respiratory chain and the production of ROS, as well as increased the transcription of mt-DNA. These effects caused a downstream activation of NF-kB. In conclusion, my results indicate that the pro-inflammatory mediator LTD4 has an important role in tumour development in the intestine by its regulation of cell proliferation and survival.