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Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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. , p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 34
Keywords [en]
Immunology, ATPase, CD59, Complement, DU145, Extracellular phosphorylation, LNCaP, PC-3, Prostasomes, Prostate cancer, Protein kinases, Tissue factor
Keywords [sv]
Immunologi
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-5779ISBN: 91-554-6238-3 (print)OAI: oai:DiVA.org:uu-5779DiVA, id: diva2:166351
Public defence
2005-05-23, Rudbeck Hall, Rudbeck Laboratory, UAS - C11, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Transfer of prostasomal CD59 to CD59-deficient red blood cells results in protection against complement mediated hemolysis
Open this publication in new window or tab >>Transfer of prostasomal CD59 to CD59-deficient red blood cells results in protection against complement mediated hemolysis
2002 In: Am J Reprod Immunol, ISSN 8755-8920, Vol. 47, no 3, p. 183-192Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-93003 (URN)
Available from: 2005-05-03 Created: 2005-05-03Bibliographically approved
2. Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck
Open this publication in new window or tab >>Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck
Show others...
2005 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, no 2, p. 105-114Article 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 the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.

METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.

RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.

CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93004 (URN)10.1002/pros.20102 (DOI)15389819 (PubMedID)
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2017-12-14Bibliographically approved
3. Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin
Open this publication in new window or tab >>Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin
2006 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 7, p. 675-686Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93005 (URN)10.1002/pros.20268 (DOI)16425202 (PubMedID)
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2017-12-14Bibliographically approved
4. Prothrombotic effect of prostasomes of metastatic cell and seminal origin
Open this publication in new window or tab >>Prothrombotic effect of prostasomes of metastatic cell and seminal origin
Show others...
2007 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 378-388Article 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.

Keywords
Coagulation, Prostasomes, Prostate cancer, Tissue factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93006 (URN)10.1002/pros.20497 (DOI)000244510000005 ()17219380 (PubMedID)
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2017-12-14Bibliographically approved

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