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Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
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2015 (engelsk)Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, nr 11, s. 3015-3022Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Prostasomes are exosomes derived from prostate epithelial cells through exocytosis by multivesicular bodies. Prostasomes have a bilayered membrane and readily interact with sperm. The membrane lipid composition is unusual with a high contribution of sphingomyelin at the expense of phosphatidylcholine and saturated and monounsaturated fatty acids are dominant. Lipid rafts are liquid-ordered domains that are more tightly packed than the surrounding non-raft phase of the bilayer. Lipid rafts are proposed to be highly dynamic, submicroscopic assemblies that float freely within the liquid disordered membrane bilayer and some proteins preferentially partition into the ordered raft domains. We asked the question whether lipid rafts do exist in prostasomes and, if so, which proteins might be associated with them. Prostasomes of density range 1.13-1.19g/mL were subjected to density gradient ultracentrifugation in sucrose fabricated by phosphate buffered saline (PBS) containing 1% Triton X-100 with capacity for banding at 1.10g/mL, i.e. the classical density of lipid rafts. Prepared prostasomal lipid rafts (by gradient ultracentrifugation) were analyzed by mass spectrometry and electron microscopy. The clearly visible band on top of 1.10g/mL sucrose in the Triton X-100 containing gradient was subjected to LC-MS/MS and more than 370 lipid raft associated proteins were identified. Several of them were involved in intraluminal vesicle formation, e.g. tetraspanins, ESCRTs and Ras-related proteins. This is the first comprehensive LC-MS/MS profiling of proteins in lipid rafts derived from exosomes. Data are available via ProteomeXchange with identifier PXD002163.

sted, utgiver, år, opplag, sider
2015. Vol. 14, nr 11, s. 3015-3022
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-261543DOI: 10.1074/mcp.M114.047530ISI: 000365636800014PubMedID: 26272980OAI: oai:DiVA.org:uu-261543DiVA, id: diva2:850604
Tilgjengelig fra: 2015-09-01 Laget: 2015-09-01 Sist oppdatert: 2018-12-11bibliografisk kontrollert
Inngår i avhandling
1. Prostasomes as Diagnostic, Prognostic and Therapeutic Vesicles
Åpne denne publikasjonen i ny fane eller vindu >>Prostasomes as Diagnostic, Prognostic and Therapeutic Vesicles
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

This thesis explores prostasomes and their ability to be used as a new diagnostic tool for prostate cancer. Alongside diagnosis, this thesis also suggests prostasomes as a tool for prognosis and therapeutic treatment in patients with prostate cancer. By further characterizing prostasomes we can identify a biomarker and also a method of visualizing and interpreting the information provided in order to conduct a correct and fast diagnosis for prostate cancer.

In Paper I, we show that the prostasomal bilayered membrane consists of lipid rafts, clusters that holds cholesterol, sphingolipids and gives receptors a rigid platform upon which to work. We compare the proteomic content of prostasome lipid rafts with the entire prostasome membrane in the search for a specific biomarker. 

In Paper II, we show that purified lipid rafts from the prostasome membrane can re-vesiculate and create new bioengineered vesicles. These new vesicles can carry different agents inside them and we find that the method is also applicable to blood cells. This suggests a new method for cell-specific delivery of drugs and cancer therapy. 

In Paper III, we further characterize the prostasome membrane, this time mapping purinergic receptors. This could be used in the development of prostate cancer treatment and to gain better understanding of how prostasomes interact with surrounding cells in their ambient environment.

In Paper IV, we investigate the difference in thymidine kinase 1 (TK1) enzyme activity between prostasomes and malignant exosomes. TK1 is considered to be a biomarker of cell proliferation and could therefore be used as a biomarker for prostate cancer diagnosis and progression.

In summary, this thesis contributes to the puzzle of how to better diagnose, prognose and treat prostate cancer. Although it is mainly pre-clinical research it opens up new possibilities for the diagnosis and treatment of prostate cancer.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1528
Emneord
Exosomes, Prostasomes, Lipid rafts, Bioengineered vesicles, Prostate cancer, Purinergic receptors, Thymidine kinase 1
HSV kategori
Forskningsprogram
Medicinsk biokemi
Identifikatorer
urn:nbn:se:uu:diva-369166 (URN)978-91-513-0541-7 (ISBN)
Disputas
2019-02-16, Universitetshuset, Sal IX, Biskopsgatan 3, Uppsala, 13:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2019-01-24 Laget: 2018-12-11 Sist oppdatert: 2019-02-18

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