leukotriene-d4 and Colorectal-Neoplasms

It has recently been demonstrated that cysteinyl leukotrienes are involved in a variety of proinflammatory and neoplastic functions. This article gives an up-to-date overview of the present knowledge of these bioactive lipid molecules. Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are applied as models of their cellular actions. It is described how signalling cascades initiated by cysteinyl leukotrienes represent alternative ways in which IBD might progress and lead to the development and propagation of CRC, and as such represent potential targets for future therapeutic regimens to manage chronic inflammatory disorders and cancer.

Topics: Cell Membrane; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Leukotriene D4; Leukotrienes; Receptors, Leukotriene; Signal Transduction

Searching for a link between inflammation and colon cancer, we have found that the inflammatory mediator leukotriene D(4) (LTD(4)), via its receptor CysLT(1), induces cyclooxygenase-2 expression, survival, and proliferation in intestinal epithelial cells. In conjunction with our previous observation that CysLT(1) receptor expression is increased in colorectal adenocarcinomas, we here found an increased nuclear localization of the CysLT(1) receptor in colorectal adenocarcinomas. This novel discovery of CysLT(1) 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 CysLT(1) receptor, but prolonged LTD(4) exposure induced its nuclear translocation in nontransformed cells. Truncation of a nuclear localization sequence abrogated this translocation as well as the LTD(4)-induced proliferative response. In accordance, nuclear CysLT(1) 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 CysLT(1) receptor localization in colorectal adenocarcinomas. The present findings indicate that LTD(4) cannot only be synthesized but also signal proliferation through nuclear CysLT(1) receptors, stressing the importance of leukotrienes in inflammation-induced colon carcinogenesis.

Topics: Adenocarcinoma; Amino Acid Sequence; Arachidonate 5-Lipoxygenase; Caco-2 Cells; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Colorectal Neoplasms; Epithelial Cells; Gene Expression Regulation, Neoplastic; Humans; Leukotriene D4; Membrane Proteins; Molecular Sequence Data; Nuclear Localization Signals; Receptors, Leukotriene; Up-Regulation