Endothelin receptor blockade inhibits molecular effectors of Kaposi's sarcoma cell invasion and tumor growth in vivo.
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.
Rosanò
Laura
L
Laboratories of Molecular Pathology and Ultrastructure and Immunology, Regina Elena Cancer Institute, and the Molecular Biology and Pathology Institute, Consiglio Nazionale delle Ricerche, Rome, Italy.
Spinella
Francesca
F
Di Castro
Valeriana
V
Nicotra
Maria Rita
MR
Albini
Adriana
A
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D017690:Cell Transplantation; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D019334:Endothelin-3 / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D019716:Tissue Inhibitor of Metalloproteinase-2; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D020782:Matrix Metalloproteinases