It is well documented that prolonged inflammatory conditions, particularly those relating to the colon, have been shown to induce
cancer. We have previously demonstrated that the pro-inflammatory mediator
leukotriene D(4) (LTD(4)) induces survival and proliferation in intestinal cells and that its receptor, CysLT(1), is upregulated in human
colon cancer tissue. Here we demonstrate, for the first time that in both Int 407 (a non-transformed human intestinal epithelial cell line) and Caco-2 cells (a human
colorectal carcinoma cell line), cytosolic
phospholipase A(2)alpha (cPLA(2)alpha) is activated and translocates to the nucleus upon LTD(4) stimulation via a
calcium-dependent mechanism that involves activation of
protein kinase C (PKC), and the
mitogen-activated protein kinases ERK1/2 and p38. We also show with a cPLA(2)alpha promoter
luciferase assay, that LTD(4) induces an increase in the transcriptional activity of cPLA(2)alpha via activation of cPLA(2)alpha and the
transcription factor NFkappaB. Interestingly we demonstrate here that both the basal and the LTD(4)-induced cPLA(2)alpha activity is elevated approximately 3-fold in Caco-2
colon cancer cells compared with Int 407 cells. The difference in basal activity was confirmed in human colon
tumor samples by the finding of a similar increase in cPLA(2)alpha activity when compared with normal colon tissue. A functional role of the increased cPLA(2)alpha activity in
tumor cells was revealed by our findings that inhibition of this
enzyme reduced both basal and LTD(4)-induced proliferation, the effects being most pronounced in Caco-2
tumor cells. The present data reveal that cPLA(2)alpha, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon
tumor growth.