Leukotriene D(4)-induced Caco-2 cell proliferation is mediated by prostaglandin E(2) synthesis

Leukotriene D(4) (LTD(4)) is a pro-inflammatory mediator formed from arachidonic acid through the action of 5-lipoxygenase (5-LOX). Its biological effects are mediated by at least two G-coupled plasmatic cysteinyl LT receptors (CysLT(1-2)R). It has been reported an upregulation of the 5-LOX pathway in tumor tissue unlike in normal colon mucosa. Colon tumors generally have an increased expression of CysLT(1)R and colon cancer patients with high expression levels of CysLT(1)R have poor prognosis. We previously observed that the cyclooxygenase pathway is involved in the control of intestinal epithelial cancer cell growth through PGE(2) production. The aim of this study was therefore to assess the effect of LTD(4) binding with CysLT(1)R on Caco-2 cell growth. We note a number of key findings from this research. We observed that at a concentration similar to that found under inflammatory conditions, LTD(4) was able to induce Caco-2 cell proliferation and DNA synthesis. Moreover, with the use of a specific receptor antagonist this study has demonstrated that the effect of LTD(4) is a result of its interaction with CystLT(1)R. We also note the possible participation of the PLC-IP(3)-Ca(2+)/DAG-PKC signaling pathways in cytosolic PLA(2) and [(3)H]AA release induced by LTD(4)-CystLT(1)R interaction. Finally, we found that the resulting activation of the AA cascade and the production of PGE(2) eicosanoid could be related to the activation of cell signaling pathways such as ERK and CREB. These findings will help facilitate our understanding of how inflammatory mediators can affect the survival and dissemination of intestinal carcinoma cells.