Endothelin receptor blockade inhibits molecular effectors of Kaposi's sarcoma cell invasion and tumor growth in vivo.

Abstract

Endothelin-1 (ET-1) and its receptors are overexpressed in human Kaposi's sarcoma lesions. Here we show that in human KS IMM cell line ET-1 increased secretion and activation of matrix-metalloproteinase-2 (MMP-2), -3, -7, -9 and -13, as well as of membrane-type 1-MMP (MT1-MMP). ET-1 and ET-3 also enhanced the expression of tissue inhibitor of MMP-2, essential for MT1-MMP-mediated MMP-2 activation. Combined addition of both ET(B) receptor (ET(B)R) and ET(A)R antagonists completely blocked the ET-1-induced MMP activity. By immunohistochemistry, we observed that ET-1 increased MMP-2 and MT1-MMP expression and their localization at the cell surface. Treatment with both antagonists resulted also in the suppression of ET-1-induced phosphorylation of focal adhesion proteins, FAK and paxillin, which are essentials for cell motility. ET-1 induced a dose-dependent enhancement in KS IMM cell migration and MMP-dependent invasiveness that were inhibited by ET-1 receptor antagonists. The small molecule, A-182086, an orally bioavailable ET(A/B)R antagonist, completely inhibited cell proliferation and tumor growth in KS IMM xenografts. These findings demonstrate that ET-1-driven autocrine loop is crucial for enhanced invasiveness of KS IMM cells and promote tumor growth in vivo. Such activities can be blocked by the ET(A/B)R antagonists, which may be effective anti-angiogenic and anti-tumor molecules for the treatment of Kaposi's sarcoma.

• Authors: Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Maria Rita Nicotra, Adriana Albini, Pier Giorgio Natali, Anna Bagnato
• Journal: The American journal of pathology (Am J Pathol) Vol. 163 Issue 2 Pg. 753-62 (Aug 2003) ISSN: 0002-9440 [Print] United States
• PMID: 12875994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Cytoskeletal Proteins
• Endothelin Receptor Antagonists
• Endothelin-1
• Endothelin-3
• PXN protein, human
• Paxillin
• Phosphoproteins
• Pxn protein, mouse
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin
• Tissue Inhibitor of Metalloproteinase-2
• Protein-Tyrosine Kinases
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• PTK2 protein, human
• Ptk2 protein, mouse
• Matrix Metalloproteinases

Topics

• Animals
• Cell Division (physiology)
• Cell Movement (physiology)
• Cell Transplantation
• Culture Media, Conditioned
• Cytoskeletal Proteins (metabolism)
• Endothelin Receptor Antagonists
• Endothelin-1 (metabolism)
• Endothelin-3 (metabolism)
• Enzyme Activation
• Female
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• Humans
• Matrix Metalloproteinases (genetics, metabolism)
• Mice
• Mice, Nude
• Paxillin
• Phosphoproteins (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin (metabolism)
• Sarcoma, Kaposi (metabolism, pathology)
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• Tumor Cells, Cultured