A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells

Searching for a link between inflammation and colon cancer, we have found that the inflammatory mediator leukotriene D4 (LTD4), via its receptor CysLT1, induces cyclooxygenase-2 expression, survival, and proliferation in intestinal epithelial cells. In conjunction with our previous observation that CysLT1 receptor expression is increased in colorectal adenocarcinomas, we here found an increased nuclear localization of the CysLT1 receptor in colorectal adenocarcinomas. This novel discovery of CysLT1 receptors in the nucleus was further analyzed. It was found to be located in the outer nuclear membrane in colon cancer cells and in the nontransformed epithelial cell line Int 407 cells by Western blot and electron microscopy. Cancer cells displayed higher amounts of the nuclear CysLT1 receptor, but prolonged LTD4 exposure induced its nuclear translocation in nontransformed cells. Truncation of a nuclear localization sequence abrogated this translocation as well as the LTD4-induced proliferative response. In accordance, nuclear CysLT1 receptors exhibited proliferative extracellular signal-regulated kinase 1/2 signaling. The significance of these experimental findings is supported by the observed correlation between the proliferative marker Ki-67 and nuclear CysLT1 receptor localization in colorectal adenocarcinomas. The present findings indicate that LTD4 cannot only be synthesized but also signal proliferation through nuclear CysLT1 receptors, stressing the importance of leukotrienes in inflammation-induced colon carcinogenesis.