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Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer Pharmacology and Informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2008 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 100, no 4, 655-662 p.Article in journal (Refereed) Published
Abstract [en]

Cancer confers a prothrombotic state and statins are associated with a lowered risk for prostate cancer in vivo by unknown mechanisms. Prostate cancer cells release tissue factor (TF)- bearing, cholesterol-rich prostasomes which are pro-coagulant in vitro and a possible source for the blood-borne TF found in prostate cancer patients.We investigated the effect of cholesterol depletion on the production of prostasomes and on the TF activity in the conditioned medium of simvastatin-treated PC3 cells. Human PC3 prostate cancer cells were treated with high and low concentrations of simvastatin for different time periods. Caspase-3 was detected with theArrayScan microscope,whereas TF mRNA and protein were analyzed by TaqMan and flow cytometry. TF activity was assessed by measuring the cleavage of a chromogenic thrombin substrate.Prostasomes were isolated by repeated centrifugations and detected and quantified by flow cytometry. A micromolar dose of simvastatin caused reduction of TF expression and induction of apoptosis in the PC3 cells.The levels of TF on the prostasomes were also decreased but the TF activity in the conditioned medium of the simvastatin-treated PC3 cells was increased due to apoptosis-dependent release of prostasomes.Treatment with a nanomolar dose of simvastatin did not induce apoptosis or alter the expression of TF but instead decreased the production and release of the prostasomes. The TF activity was reduced in parity with the decline in prostasome release. In conclusion, in prostate cancer, a nanomolar dose of simvastatin may have an anti-thrombotic effect due to decreased levels of circulating TF-bearing prostasomes.

Place, publisher, year, edition, pages
2008. Vol. 100, no 4, 655-662 p.
Keyword [en]
Apoptosis, deep vein thrombosis, malignancy, microparticles, tissue factor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97674DOI: 10.1160/TH08-03-0173ISI: 000260216000022PubMedID: 18841289OAI: oai:DiVA.org:uu-97674DiVA: diva2:172705
Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2011-03-17Bibliographically 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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