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The tissue factor signaling complexes prevent caspase-8-induced apoptosis independently of PAR-1, PAR-2, and GRP78
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-97676OAI: oai:DiVA.org:uu-97676DiVA: diva2:172707
Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
Open this publication in new window or tab >>Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. TF is over-expressed on many malignant cells and apart from increasing the risk of thrombosis, the presence of TF/FVIIa also promotes the progression of cancer and metastasis by intracellular signaling. TF expressing microparticles (MP) are, moreover, often found in the circulation of cancer patients.

Aim: The aim of this thesis was to study different aspects of TF activity, e.g. the importance of procoagulant MP and TF-induced intracellular signaling pathways, with focus on cell migration (chemotaxis) and apoptosis.

Results: The TF signaling complexes were shown to prevent apoptosis induced by serum starvation and TRAIL in cancer cells by reduced activation of caspase-8 in a PI3k/AKT-dependent manner. FVIIa also decreased transcription of pro-apoptotic genes in cancer cells treated with TRAIL. Simvastatin triggered apoptosis by transcriptional reduction of BCL-2 due to cytosolic retention of NFκB. Simvastatin also inactivated the PI3k/AKT pathway and reduced the production of the MP-like prostasomes which, respectively, impaired the anti-apoptotic signaling by TF and reduced the procoagulant activity in the vicinity of prostate cancer cells. Intracellular events conducted by the TF/FVIIa complex selectively enhanced PDGF-BB induced chemotaxis which was partly explained by the TF/FVIIa-induced transactivation of the PDGFβ-receptor. This was dependent on Src-family members and engagement of PAR2.

Conclusions: The results presented in this thesis extend the current knowledge of TF-mediated signaling. We report the TF complexes to govern the extrinsic pathway of apoptosis, present data on FVIIa-dependent regulation of apoptosis-related genes, and exclude known surface proteins as transmitters of the anti-apoptotic signals. We moreover describe TF/FVIIa to transactivate the PDGFβ-receptor and play a decisive role in the potentiated chemotaxis toward PDGF-BB in a number of cell types. Finally, we explain the mechanism behind simvastatin-induced apoptosis in cancer cells and how statins interfere with TF-dependent signaling and coagulation.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 391
Keyword
Tissue factor, Apoptosis, Migration, Chemotaxis, Simvastatin, Platelet Derived Growth Factor, Cell Signaling, Microparticles, Prostasomes, Trombosis, Coagulation, Prostate Cancer, Breast Cancer, Caspase-3, Caspase-8, NFkappaB, PAR2, Transactivation, Monocytes
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-9335 (URN)978-91-554-7317-4 (ISBN)
Public defence
2008-11-21, Enghoffsalen, Akademiska sjukhuset, Ingång 50, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-10-30 Created: 2008-10-30Bibliographically approved

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