Carcinogenesis Advance Access originally published online on June 23, 2005
Carcinogenesis 2005 26(11):1988-1998; doi:10.1093/carcin/bgi159
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Carcinogenesis vol.26 no.11 © Oxford University Press 2005; all rights reserved.
Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells
Experimental Pathology, The Department of Laboratory Medicine and 1 Surgery, The Department of Clinical Sciences, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden
* To whom correspondence should be addressed. Tel: +46 40 337223; Fax: +46 40 337353; Email: Anita.Sjolander{at}med.lu.se
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 D4 (LTD4) induces survival and proliferation in intestinal cells and that its receptor, CysLT1, 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 A2
(cPLA2) is activated and translocates to the nucleus upon LTD4 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 cPLA2 promoter luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA2 via activation of cPLA2 and the transcription factor NF
B. Interestingly we demonstrate here that both the basal and the LTD4-induced cPLA2 activity is elevated 
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 cPLA2 activity when compared with normal colon tissue. A functional role of the increased cPLA2 activity in tumor cells was revealed by our findings that inhibition of this enzyme reduced both basal and LTD4-induced proliferation, the effects being most pronounced in Caco-2 tumor cells. The present data reveal that cPLA2, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon tumor growth.
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