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Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2006 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 7, 675-686 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.

METHODS:

The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.

RESULTS:

Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.

CONCLUSIONS:

These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.

Place, publisher, year, edition, pages
2006. Vol. 66, no 7, 675-686 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93005DOI: 10.1002/pros.20268PubMedID: 16425202OAI: oai:DiVA.org:uu-93005DiVA: diva2:166349
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
Opponent
Supervisors
Available from: 2005-05-03 Created: 2005-05-03Bibliographically approved

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Nilsson, BoNilsson Ekdahl, Kristina

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