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Carcinogenesis Advance Access published online on June 23, 2005
Carcinogenesis, doi:10.1093/carcin/bgi159
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 8, 2005
Revised June 10, 2005
Accepted June 15, 2005

CARCINOGENESIS

Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells

Ladan Parhamifar 1, Bengt Jeppsson 2, and Anita Sjölander 1*

1 Experimental Pathology, the Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden
2 Surgery, the Department of Clinical Sciences, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden

* To whom correspondence should be addressed.
Anita Sjölander, E-mail: Anita.Sjolander{at}exppat.mas.lu.se


  Abstract

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 up-regulated 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{alpha} (cPLA2{alpha}) is activated and translocates to the nucleus upon LTD4 stimulation via a calcium-dependent mechanism that involves activation of protein kinase C (PKC), the mitogen-activated protein kinases ERK1/2 and p38. We also show with a cPLA2{alpha} promotor luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA2{alpha} via activation of cPLA2{alpha} and the transcription factor NF{kappa}B. Interestingly here we demonstrate that both the basal and the LTD4-induced cPLA2{alpha} activity is elevated almost three fold in Caco-2 colon cancer cells compared to Int 407 cells. The difference in basal activity was confirmed in human colon tumor samples by the finding of a similar increase in cPLA2{alpha} activity when compared with normal colon tissue. A functional role of the increased cPLA2{alpha} 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{alpha}, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon tumor growth.

Keywords: Cytosolic Phospholipase A2; Leukotriene D4; Colon cancer; Inflammation; Proliferation; MAPK.
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