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

Parhamifar, Ladan LU ; Jeppsson, Bengt LU and Sjölander, Anita LU (2005) In Carcinogenesis 26(Jun 23). p.1988-1998
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 D-4 (LTD4) 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 LTD4 stimulation via a calcium-dependent mechanism that involves activation of protein kinase C (PKC), and the... (More)
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 (LTD4) 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 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 cPLA(2)alpha promoter luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA(2)alpha via activation of cPLA(2)alpha and the transcription factor NF kappa B. Interestingly we demonstrate here that both the basal and the LTD4-induced cPLA(2)alpha activity is elevated similar to 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 LTD4-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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Carcinogenesis
volume
26
issue
Jun 23
pages
1988 - 1998
publisher
Oxford University Press
external identifiers
  • pmid:15975962
  • wos:000232746500019
  • scopus:27844451525
ISSN
0143-3334
DOI
10.1093/carcin/bgi159
language
English
LU publication?
yes
id
e4abe0d9-b658-4762-8b7b-14949c7730e4 (old id 139782)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15975962&dopt=Abstract
date added to LUP
2007-07-26 14:22:22
date last changed
2017-01-01 05:11:06
@article{e4abe0d9-b658-4762-8b7b-14949c7730e4,
  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 D-4 (LTD4) 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 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 cPLA(2)alpha promoter luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA(2)alpha via activation of cPLA(2)alpha and the transcription factor NF kappa B. Interestingly we demonstrate here that both the basal and the LTD4-induced cPLA(2)alpha activity is elevated similar to 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 LTD4-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.},
  author       = {Parhamifar, Ladan and Jeppsson, Bengt and Sjölander, Anita},
  issn         = {0143-3334},
  language     = {eng},
  number       = {Jun 23},
  pages        = {1988--1998},
  publisher    = {Oxford University Press},
  series       = {Carcinogenesis},
  title        = {Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells.},
  url          = {http://dx.doi.org/10.1093/carcin/bgi159},
  volume       = {26},
  year         = {2005},
}