Abstract
Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acquired Immunodeficiency Syndrome / metabolism
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Acquired Immunodeficiency Syndrome / virology
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Androstadienes / pharmacology
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Animals
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Antigens, CD / metabolism*
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Cadherins / metabolism*
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Capillary Permeability / drug effects
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Cell Line
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Chromones / pharmacology
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Cinnamates / pharmacology
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Endothelial Cells / drug effects
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Endothelial Cells / virology
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Enzyme Inhibitors / pharmacology
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Female
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Furans / pharmacology
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Herpesvirus 8, Human*
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Humans
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Indoles / pharmacology
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Intercellular Junctions / drug effects
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Intercellular Junctions / metabolism
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Mice
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Mice, Nude
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Quinoxalines / pharmacology
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RNA, Small Interfering / genetics
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Receptors, Chemokine / metabolism*
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Sarcoma, Kaposi / drug therapy
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Sarcoma, Kaposi / pathology
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Sarcoma, Kaposi / virology*
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Skin / metabolism
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Skin / virology
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Skin Neoplasms / drug therapy
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Skin Neoplasms / virology*
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Sulfonamides / pharmacology
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Thiazolidinediones / pharmacology
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Wortmannin
Substances
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5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
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Androstadienes
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Antigens, CD
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Cadherins
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Chromones
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Cinnamates
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Enzyme Inhibitors
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Furans
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G protein-coupled receptor, Human herpesvirus 8
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Indoles
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Morpholines
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PI103
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Pyridines
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Pyrimidines
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Quinoxalines
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RNA, Small Interfering
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Receptors, Chemokine
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SU 1498
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SU 6656
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Sulfonamides
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Thiazolidinediones
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cadherin 5
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Phosphatidylinositol 3-Kinases
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Wortmannin