Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells.
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.
Experimental Pathology, The Department of Laboratory Medicine and Surgery, Lund University, Malmö University Hospital, Malmö, Sweden.
Ladan
L
Parhamifar
Bengt
B
Jeppsson
Anita
A
Sjölander
D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D054513:Group IV Phospholipases A2; D006801:Humans; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism; D017998:Leukotriene D4 / Q000494:pharmacology*; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport
D016328:NF-kappa B; D017998:Leukotriene D4; D008156:Luciferases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D002118:Calcium