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The urokinase-type plasminogen activator, its receptor and u-PA inhibitor type-1 affect in vitro growth and invasion of Kaposi's sarcoma and capillary endothelial cells: role of HIV-Tat protein.
Int J Oncol. 2005 Jul; 27(1):223-35.IJ

Abstract

The aggressive and malignant nature of AIDS-associated Kaposi's sarcoma (KS) lesions have largely been ascribed to Tat, the HIV-1 transactivator protein. Among other activities, HIV-Tat induces the migration and invasion of KS and endothelial cells. Since cell invasion is strictly correlated to the activity of lytic enzymes, we elucidated the role of the cell-associated plasminogen activation system in Tat-dependent and in constitutive invasion and proliferation of KS and of microvascular endothelial cells (MVEC). We demonstrate that KS cells and MVEC express the u-PA receptor (u-PAR) and release plasminogen activators and plasminogen activator inhibitor type-1 (PAI-1). The urokinase-type plasminogen activator (u-PA) is chemotactic, chemoinvasive and mitogenic for KS cells and for MVEC. Conditioned medium from KS cells induced invasion and proliferation of MVEC through the u-PA/u-PAR system. Tat is motogenic and mitogenic on KS cells and MVEC, and stimulates morphogenesis of MVEC. These activities were inhibited following antagonization of u-PA and u-PAR, which also reduced constitutive proliferation and invasion of KS cells and MVEC. These data indicate that the u-PA/u-PAR/PAI-1 system is involved in KS-induced endothelial cell invasion, proliferation, and differentiation. Further, exogenous Tat protein could up-regulate the fibrinolytic system, increasing its influence on KS and endothelial cell proliferation and migration, potentially promoting KS progression. These observations suggest the potential for application of u-PA/u-PAR system inhibitors for control of AIDS-associated KS, that has a high risk of recurrence with highly active antiretroviral therapy failure, and of other KS forms.

Authors+Show Affiliations

Margheri F
Department of Experimental Pathology and Oncology, University of Florence, Italy.
D'Alessio S
No affiliation info available
Serratì S
No affiliation info available
Pucci M
No affiliation info available
Del Rosso A
No affiliation info available
Benelli R
No affiliation info available
Ferrari N
No affiliation info available
Noonan DM
No affiliation info available
Albini A
No affiliation info available
Fibbi G
No affiliation info available
Del Rosso M
No affiliation info available

MeSH

Antibodies, MonoclonalAntiretroviral Therapy, Highly ActiveCapillariesCell Line, TumorCell ProliferationCollagenCulture Media, ConditionedDrug CombinationsEndothelium, VascularEnzyme-Linked Immunosorbent AssayGene Products, tatHumansLamininMicrocirculationProteoglycansReceptors, Cell SurfaceReceptors, Urokinase Plasminogen ActivatorReverse Transcriptase Polymerase Chain ReactionSarcoma, KaposiTemperatureTime FactorsUrokinase-Type Plasminogen Activator

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15942664

Citation

Margheri, Francesca, et al. "The Urokinase-type Plasminogen Activator, Its Receptor and u-PA Inhibitor Type-1 Affect in Vitro Growth and Invasion of Kaposi's Sarcoma and Capillary Endothelial Cells: Role of HIV-Tat Protein." International Journal of Oncology, vol. 27, no. 1, 2005, pp. 223-35.
Margheri F, D'Alessio S, Serratì S, et al. The urokinase-type plasminogen activator, its receptor and u-PA inhibitor type-1 affect in vitro growth and invasion of Kaposi's sarcoma and capillary endothelial cells: role of HIV-Tat protein. Int J Oncol. 2005;27(1):223-35.
Margheri, F., D'Alessio, S., Serratì, S., Pucci, M., Del Rosso, A., Benelli, R., Ferrari, N., Noonan, D. M., Albini, A., Fibbi, G., & Del Rosso, M. (2005). The urokinase-type plasminogen activator, its receptor and u-PA inhibitor type-1 affect in vitro growth and invasion of Kaposi's sarcoma and capillary endothelial cells: role of HIV-Tat protein. International Journal of Oncology, 27(1), 223-35.
Margheri F, et al. The Urokinase-type Plasminogen Activator, Its Receptor and u-PA Inhibitor Type-1 Affect in Vitro Growth and Invasion of Kaposi's Sarcoma and Capillary Endothelial Cells: Role of HIV-Tat Protein. Int J Oncol. 2005;27(1):223-35. PubMed PMID: 15942664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The urokinase-type plasminogen activator, its receptor and u-PA inhibitor type-1 affect in vitro growth and invasion of Kaposi's sarcoma and capillary endothelial cells: role of HIV-Tat protein. AU - Margheri,Francesca, AU - D'Alessio,Silvia, AU - Serratì,Simona, AU - Pucci,Marco, AU - Del Rosso,Angela, AU - Benelli,Roberto, AU - Ferrari,Nicoletta, AU - Noonan,Douglas M, AU - Albini,Adriana, AU - Fibbi,Gabriella, AU - Del Rosso,Mario, PY - 2005/6/9/pubmed PY - 2005/9/17/medline PY - 2005/6/9/entrez SP - 223 EP - 35 JF - International journal of oncology JO - Int J Oncol VL - 27 IS - 1 N2 - The aggressive and malignant nature of AIDS-associated Kaposi's sarcoma (KS) lesions have largely been ascribed to Tat, the HIV-1 transactivator protein. Among other activities, HIV-Tat induces the migration and invasion of KS and endothelial cells. Since cell invasion is strictly correlated to the activity of lytic enzymes, we elucidated the role of the cell-associated plasminogen activation system in Tat-dependent and in constitutive invasion and proliferation of KS and of microvascular endothelial cells (MVEC). We demonstrate that KS cells and MVEC express the u-PA receptor (u-PAR) and release plasminogen activators and plasminogen activator inhibitor type-1 (PAI-1). The urokinase-type plasminogen activator (u-PA) is chemotactic, chemoinvasive and mitogenic for KS cells and for MVEC. Conditioned medium from KS cells induced invasion and proliferation of MVEC through the u-PA/u-PAR system. Tat is motogenic and mitogenic on KS cells and MVEC, and stimulates morphogenesis of MVEC. These activities were inhibited following antagonization of u-PA and u-PAR, which also reduced constitutive proliferation and invasion of KS cells and MVEC. These data indicate that the u-PA/u-PAR/PAI-1 system is involved in KS-induced endothelial cell invasion, proliferation, and differentiation. Further, exogenous Tat protein could up-regulate the fibrinolytic system, increasing its influence on KS and endothelial cell proliferation and migration, potentially promoting KS progression. These observations suggest the potential for application of u-PA/u-PAR system inhibitors for control of AIDS-associated KS, that has a high risk of recurrence with highly active antiretroviral therapy failure, and of other KS forms. SN - 1019-6439 UR - https://www.unboundmedicine.com/medline/citation/15942664/The_urokinase_type_plasminogen_activator_its_receptor_and_u_PA_inhibitor_type_1_affect_in_vitro_growth_and_invasion_of_Kaposi's_sarcoma_and_capillary_endothelial_cells:_role_of_HIV_Tat_protein_ DB - PRIME DP - Unbound Medicine ER -