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LTD4 signalling via beta-catenin: a possible link between inflammation and cancer

Mezhybovska, Maryna LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:124.
Abstract
The pro-inflammatory mediator LTD4 is an important component in the pathogenesis of inflammatory conditions as inflammatory bowel diseases. Patients suffering from inflammatory bowel diseases face an increased risk of intestinal cancer development. Therefore it is important to investigate the role of LTD4 signalling in cancer development and progression.

In this thesis I show that there is an endogenous production of LTD4 in both non-transformed and cancer intestinal epithelial cells leading to a continuous activation of the CysLT1 receptor. The activation of this receptor signals increased proliferation and increased survival. My finding that CysLT1 receptor signalling leads to accumulation of b-catenin in the nuclei and... (More)
The pro-inflammatory mediator LTD4 is an important component in the pathogenesis of inflammatory conditions as inflammatory bowel diseases. Patients suffering from inflammatory bowel diseases face an increased risk of intestinal cancer development. Therefore it is important to investigate the role of LTD4 signalling in cancer development and progression.

In this thesis I show that there is an endogenous production of LTD4 in both non-transformed and cancer intestinal epithelial cells leading to a continuous activation of the CysLT1 receptor. The activation of this receptor signals increased proliferation and increased survival. My finding that CysLT1 receptor signalling leads to accumulation of b-catenin in the nuclei and activation of the transcription factor TCF/LEF is in line with the ability of this receptor to promote cell proliferation. However, I also found that CysLT1 receptor activation caused b-catenin to translocate to the mitochondria where it associated with the survival protein Bcl-2. In addition, I observed that LTD4-induced activation of the CysLT1 receptor or overexpression of b-catenin in both non-transformed and cancer intestinal epithelial cells enhanced the activity of the respiratory chain and the production of ROS, as well as increased the transcription of mt-DNA. These effects caused a downstream activation of NF-kB. In conclusion, my results indicate that the pro-inflammatory mediator LTD4 has an important role in tumour development in the intestine by its regulation of cell proliferation and survival. (Less)
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author
supervisor
opponent
  • Prof Näthke, Inke, Division of Cell and Developmental Biology, University of Dundee, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
LTD4, beta-catenin, colorectal cancer, CysLT1R, proliferation, inflammation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:124
pages
77 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Pathology Building, Entrance 78, U-MAS, Malmö
defense date
2008-11-07 13:00
ISSN
1652-8220
ISBN
978-91-86059-77-4
language
English
LU publication?
yes
id
ca733849-911f-4fe6-9e2f-bb2398ca9b32 (old id 1258080)
date added to LUP
2008-10-21 15:43:29
date last changed
2016-09-19 08:44:46
@phdthesis{ca733849-911f-4fe6-9e2f-bb2398ca9b32,
  abstract     = {The pro-inflammatory mediator LTD4 is an important component in the pathogenesis of inflammatory conditions as inflammatory bowel diseases. Patients suffering from inflammatory bowel diseases face an increased risk of intestinal cancer development. Therefore it is important to investigate the role of LTD4 signalling in cancer development and progression. <br/><br>
In this thesis I show that there is an endogenous production of LTD4 in both non-transformed and cancer intestinal epithelial cells leading to a continuous activation of the CysLT1 receptor. The activation of this receptor signals increased proliferation and increased survival. My finding that CysLT1 receptor signalling leads to accumulation of b-catenin in the nuclei and activation of the transcription factor TCF/LEF is in line with the ability of this receptor to promote cell proliferation. However, I also found that CysLT1 receptor activation caused b-catenin to translocate to the mitochondria where it associated with the survival protein Bcl-2. In addition, I observed that LTD4-induced activation of the CysLT1 receptor or overexpression of b-catenin in both non-transformed and cancer intestinal epithelial cells enhanced the activity of the respiratory chain and the production of ROS, as well as increased the transcription of mt-DNA. These effects caused a downstream activation of NF-kB. In conclusion, my results indicate that the pro-inflammatory mediator LTD4 has an important role in tumour development in the intestine by its regulation of cell proliferation and survival.},
  author       = {Mezhybovska, Maryna},
  isbn         = {978-91-86059-77-4},
  issn         = {1652-8220},
  keyword      = {LTD4,beta-catenin,colorectal cancer,CysLT1R,proliferation,inflammation},
  language     = {eng},
  pages        = {77},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {LTD4 signalling via beta-catenin: a possible link between inflammation and cancer},
  volume       = {2008:124},
  year         = {2008},
}