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(American Journal of Pathology. 2003;163:753-762.)
© 2003 American Society for Investigative Pathology

Endothelin Receptor Blockade Inhibits Molecular Effectors of Kaposi’s Sarcoma Cell Invasion and Tumor Growth in Vivo

Laura Rosanò^*, Francesca Spinella^*, Valeriana Di Castro^*, Maria Rita Nicotra, Adriana Albini, Pier Giorgio Natali and Anna Bagnato^*

From the Laboratories of Molecular Pathology and Ultrastructure^* and Immunology, Regina Elena Cancer Institute, and the Molecular Biology and Pathology Institute, Consiglio Nazionale delle Ricerche, Rome; and National Institute for Cancer Research, Center of Advanced Biotechnology, Genoa, Italy

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_BR) and ET_AR 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/BR 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/BR antagonists, which may be effective anti-angiogenic and anti-tumor molecules for the treatment of Kaposi’s sarcoma.

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