Influence of leukotriene D4 and cyclooxygenase-2 on cell survival

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The pro-inflammatory effect of leukotrienes is an important element in the pathogenesis of multiple disorders, including asthma and inflammatory bowel diseases (IBD). A serious concern for IBD patients is the increased risk of developing colorectal cancer and since there seems to be a general connection between inflammation and cancer we hypothesised that LTD4 induced signalling events could be involved in increasing the tumourgenic potential of cells. Another important player in colorectal carcinogenesis, as well as in inflammation is the inducible cyclooxygenase isoform COX-2. Inhibition of this enzyme reduces cancer risk and it is highly elevated in tumour tissue. We treated non-transformed intestinal epithelial cells with LTD4 and found that this led to increased expression of COX-2. Additionally, the anti-apoptotic protein Bcl-2 was elevated prompting us to study the effect of LTD4 on survival and apoptosis. We could show that inhibition of COX-2 causes increased apoptosis, mediated through activation of caspase-8, cleavage of Bid and mitochondrial release of cytochrome c. All these events could be reversed by the addition of LTD4, which even could increase cell survival above basal level. We furthermore detected a novel LTD4-induced association between Bcl-2 and the multifacetted protein b-catenin that may encompass a new mode of influencing cell survival. These effects of LTD4 were shown to be mediated through the G-protein coupled receptor, CysLT1 and this strongly indicates that inflammatory mediators such as LTD4 may have large impacts on the state of cell survival regulation.

Details

Authors
  • Katarina Wikström
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • pathological anatomy, Patologi (allmän), General pathology, colorectal cancer, inflammation, apoptosis, LTD4, COX-2, patologisk anatomi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2003 Jan 31
Publisher
  • Katarina Wikström, Experimental Pathology, Lund University, U-MAS, Entrance 78, 205 02 Malmö,
Print ISBNs91-628-5520-4
Publication statusPublished - 2003
Publication categoryResearch

Bibliographic note

Defence details Date: 2003-01-31 Time: 10:15 Place: Main lecture hall, Pathology building, Entrance 78, U-MAS, Malmö External reviewer(s) Name: Nigam, Santosh Title: Professor Affiliation: [unknown] --- Article: John F. Öhd, Katarina Wikström and Anita Sjölander. Leukotrienes induce cell-survival signaling in intestinal epithelial cells.Gastroenterology. 119; 1007-1018, 2000. Article: Katarina Wikström, Maria Juhas and Anita Sjölander. The anti-apoptotic effect of Leukotriene D4 involves prevention of Caspase-8 activation and Bid cleavage. Biochemical Journal. In press. Article: Katarina Wikström, John F. Öhd and Anita Sjölander. Regulation of Leukotriene Dependent Induction of Cyclooxygenase-2 and Bcl-2.Submitted. Article: Katarina Wikström, John F. Öhd, Maryna Mezhybovska and Anita Sjölander. Association between BCL-2 and b-catenin Ð A Novel Role for BCL-2 in LTD4-induced Cell Survival Signalling in Intestinal Epithelial Cells.Manuscript.