Signaling and regulation of cysteinyl leukotriene receptors in intestinal epithelial cells and colon cancer

Sammanfattning: Colorectal cancer is the third most common type of cancer, and the second leading cause of cancer-related deaths in the Western world. Chronic inflammation, such as inflammatory bowel diseases (IBD), increases the risk of cancer. Cysteinyl leukotrienes are pro-inflammatory mediators that are involved in IBD. They are ligands to the G-protein coupled receptors CysLT1R and CysLT2R, of which CysLT1R is associated with poor prognosis and CysLT2R with good prognosis for colorectal cancer patients. Signaling through CysLT1R results in increased proliferation, survival and migration of intestinal epithelial cells, whereas signaling through CysLT2R leads to differentiation of colorectal cancer cells. My main findings have been that 1) Leukotriene D4 (LTD4) induces intestinal epithelial cell proliferation by activating the mitogenic JNK / AP-1 pathway; 2) The mitogen EGF, involved in cancer progression, down-regulates CysLT2R expression and is inversely correlated with CysLT2R in a colorectal cancer tissue array, while 3) the anti-tumorigenic agents all-trans retinoic acid and interferon alpha up-regulate CysLT2R expression in colorectal cancer cells; 4) LTC4, a ligand for CysLT2R, inhibits migration of colorectal cancer cells; 5) Intestinal epithelial and colorectal cancer cells express enzymes and receptors of the cysteinyl leukotriene and prostaglandin pathways; and 6) The pro-tumorigenic cytokine TNF-alpha up-regulates CysLT1R while down-regulating CysLT2R. These studies provide more evidence that CysLT1R and CysLT2R have opposite functions in colon cancer progression, and we now know how to regulate their expression. This thesis provides a basic understanding on the role and regulation of the cysteinyl leukotriene receptors, which is useful for designing future therapies of colorectal cancer.