| 1. |
- Parhamifar, Ladan, et al.
(författare)
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Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells.
- 2005
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 26:Jun 23, s. 1988-1998
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Parhamifar, Ladan, et al.
(författare)
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Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer.
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| 3. |
- Parhamifar, Ladan
(författare)
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Signalling and trafficking of the cysteinyl leukotriene receptors in intestinal epithelial cells
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammation is a response to injury or pathogen invasion. A large proportion of the bodie's immune system is centred in the gastrointestinal tract (GI). Prolonged inflammatory conditions of the GI have been suggested to increase the risk for developing colon cancer. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4 are inflammatory mediators that can bind to four known receptors, two of which are the CysLT1R and CysLT2R. Inhibitors of the CysLT1R are currently used in the clinic as asthma medication. LTD4 has been shown to induce cell proliferation, survival and migration in intestinal epithelial cells (Int407) via the CysLT1R. These mechanisms are often used by cancer cells to surive and spread. Furthermore, increased expression of the CysLT1R in colon cancer patient material is correlated with a poorer survival prognosis. Conversley, increased expression of the CysLT2R is correlated with a better survival prognosis. The aim of this thesis was therefore to explore the signalling and trafficking of the cysLT1R and CysLT2R. Our results demonstrate that LTD4 via the CysLT1R can activate the enzyme cPLA2-alpha. This enzyme releases arachidonic acid, the precursor of CysLTs, from the cell membranes, upon activation. One major regulatory mechanism of GPCRs is the internalization from cell membrane upon activation. We demonstrate how LTD4 mainly internalizes CysLT1R and accumulates this receptor at the nuclear membrane and that LTC4 internalizes both the CysLT1R and CysLT2R. This information is valuable in developing potential drugtargets aqainst CysLT1 and CysLT2 in cancer and inflammation.
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| 4. |
- Yudina, Yulyana, et al.
(författare)
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Regulation of the eicosanoid pathway by tumour necrosis factor alpha and leukotriene D(4) in intestinal epithelial cells.
- 2008
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278. ; 79:6, s. 223-231
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Tidskriftsartikel (refereegranskat)abstract
- In this study the mRNA and protein levels of the key enzymes involved in eicosanoid biosynthesis and the cysteinyl leukotriene receptors (CysLT(1)R and CysLT(2)R) have been analysed in non-transformed intestinal epithelial and colon cancer cell lines. Our results revealed that tumour necrosis factor alpha (TNF-alpha), and leukotriene D(4) (LTD(4)), which are inflammatory mediators implicated in carcinogenesis, stimulated an increase of cyclooxygenase-2 (COX-2), in non-transformed epithelial cells, and 5-lipoxygenase (5-LO) in both non-transformed and cancer cell lines. Furthermore, these mediators also stimulated an up-regulation of LTC(4) synthase in cancer cells as well as non-transformed cells. We also observed an endogenous production of CysLTs in these cells. TNF-alpha and LTD(4), to a lesser extent, up-regulate the CysLT(1)R levels. Interestingly, TNF-alpha also reduced CysLT(2)R expression in cancer cells. Our results demonstrate that inflammatory mediators can cause intestinal epithelial cells to up-regulate the expression of enzymes needed for the biosynthesis of eicosanoids, including the cysteinyl leukotrienes, as well as the signal transducing proteins, the CysLT receptors, thus providing important mechanisms for both maintaining inflammation and for tumour progression.
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