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Prothrombotic effect of prostasomes of metastatic cell and seminal origin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
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2007 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, 378-388 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.

Place, publisher, year, edition, pages
2007. Vol. 67, no 4, 378-388 p.
Keyword [en]
Coagulation, Prostasomes, Prostate cancer, Tissue factor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93006DOI: 10.1002/pros.20497ISI: 000244510000005PubMedID: 17219380OAI: oai:DiVA.org:uu-93006DiVA: diva2:166350
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer
Open this publication in new window or tab >>Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified.

Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, viz. complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes.

In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 34
Keyword
Immunology, ATPase, CD59, Complement, DU145, Extracellular phosphorylation, LNCaP, PC-3, Prostasomes, Prostate cancer, Protein kinases, Tissue factor, Immunologi
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-5779 (URN)91-554-6238-3 (ISBN)
Public defence
2005-05-23, Rudbeck Hall, Rudbeck Laboratory, UAS - C11, Uppsala, 13:15
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Available from: 2005-05-03 Created: 2005-05-03Bibliographically approved

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Babiker, Adil A.Hamad, Osama A.Sanchez, JavierNilsson, BoNilsson Ekdahl, Kristina

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