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

Francesca Margheri, Silvia D'Alessio, Simona Serrati, Marco Pucci, Angela Del Rosso, Roberto Benelli, Nicoletta Ferrari, Douglas M. Noonan, Adriana Albini, Gabriella Fibbi, Mario Del Rosso

Research output: Contribution to journalArticle

Abstract

The aggressive and malignant nature of AIDSassociated 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.

Original languageEnglish
Pages (from-to)223-235
Number of pages13
JournalInternational Journal of Oncology
Volume27
Issue number1
Publication statusPublished - Jul 2005

Fingerprint

Human Immunodeficiency Virus tat Gene Products
Urokinase Plasminogen Activator Receptors
Kaposi's Sarcoma
Plasminogen Activator Inhibitor 1
Urokinase-Type Plasminogen Activator
Endothelial Cells
Growth
In Vitro Techniques
Human Immunodeficiency Virus rev Gene Products
Cell Proliferation
tat Gene Products
Plasminogen Activators
Plasminogen
Highly Active Antiretroviral Therapy
Conditioned Culture Medium

Keywords

  • Angiogenesis
  • HIV-1
  • Kaposi's sarcoma
  • Plasminogen activator inhibitor type-1
  • Tat
  • u-PA receptor
  • Urokinase-type plasminogen activator

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{23f6f66afb81438ba8b1aa019dbaa752,
title = "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",
abstract = "The aggressive and malignant nature of AIDSassociated 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.",
keywords = "Angiogenesis, HIV-1, Kaposi's sarcoma, Plasminogen activator inhibitor type-1, Tat, u-PA receptor, Urokinase-type plasminogen activator",
author = "Francesca Margheri and Silvia D'Alessio and Simona Serrati and Marco Pucci and {Del Rosso}, Angela and Roberto Benelli and Nicoletta Ferrari and Noonan, {Douglas M.} and Adriana Albini and Gabriella Fibbi and {Del Rosso}, Mario",
year = "2005",
month = "7",
language = "English",
volume = "27",
pages = "223--235",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "1",

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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

T2 - Role of HIV-Tat protein

AU - Margheri, Francesca

AU - D'Alessio, Silvia

AU - Serrati, 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 - 2005/7

Y1 - 2005/7

N2 - The aggressive and malignant nature of AIDSassociated 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.

AB - The aggressive and malignant nature of AIDSassociated 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.

KW - Angiogenesis

KW - HIV-1

KW - Kaposi's sarcoma

KW - Plasminogen activator inhibitor type-1

KW - Tat

KW - u-PA receptor

KW - Urokinase-type plasminogen activator

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JO - International Journal of Oncology

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