Journal Article

Activation of cPLA<sub>2</sub> is required for leukotriene D<sub>4</sub>-induced proliferation in colon cancer cells

Ladan Parhamifar, Bengt Jeppsson and Anita Sjölander

in Carcinogenesis

Volume 26, issue 11, pages 1988-1998
Published in print November 2005 | ISSN: 0143-3334
Published online June 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi159
Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells

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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 A2α (cPLA2α) 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 cPLA2α promoter luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA2α via activation of cPLA2α and the transcription factor NFκB. Interestingly we demonstrate here that both the basal and the LTD4-induced cPLA2α 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 cPLA2α activity when compared with normal colon tissue. A functional role of the increased cPLA2α 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 cPLA2α, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon tumor growth.

Keywords: 5-LO, 5-lipoxygenase; AA, arachidonic acid; Caco-2 cells, a human colorectal carcinoma cell line; cPLA2α, cytosolic phospholipase A2α; COX, cyclooxygenase; IBD, inflammatory bowel diseases; Int 407, a non-transformed human intestinal epithelial cell line; LTD4, leukotriene D4; MAPK, mitogen-activated protein kinases; NSAID, non-steroidal anti-inflammatory drug; NFκB, nuclear factor kappa B; PKC, protein kinase C; PTX, pertussis toxin.

Journal Article.  8722 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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