An increased expression of cysteinyl leukotriene 2 receptor in colorectal adenocarcinomas correlates with high differentiation

Increased levels of inflammatory mediators such as cystenyl leukotrienes (CysLT) have been found in and around tumors. These data, along with our previous observation that the G-protein-coupled receptor CysLT(1)R, which signals survival and proliferation, is up-regulated in colon cancer, suggest an important role for CysLT(1)R in tumor development. The objective of this study was to examine the expression and function of the low-affinity CysLT(2) receptor (CysLT(2)R) in colon cancer. We found lower expression levels of CysLT(2)R compared with CysLT(1)R in cancer cell lines as well as clinical tumor material. Interestingly, CysLT(2)R, like CysLT(1)R, was found to be one of few G-protein-coupled receptors that are located both at the plasma membrane and the nuclear membrane. No effect of CysLT(2)R signaling on cell proliferation was observed, nor was there a correlation between CysLT2R and different proliferation markers such as KI-67 and cyclooxygenase-2 in the tumor material. Instead, we found that activation of this receptor in colon cancer cells led to cellular differentiation similar to the effects of butyrate treatment. In accordance with this finding, we found that reduced expression of CysLT(2)R in colon cancer was associated with poor prognosis. We report the novel finding that CysLT(2)R signaling leads to terminal differentiation of colon carcinoma cells and growth inhibition, and that its expression is relatively high in less malignant forms of colon cancer. These data suggest that the balance between these two receptors is important for tumor progression and disease outcome.