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, Anna Bagnato

Research output: Contribution to journalArticle

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 ETB receptor (ETBR) and ETAR 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 ETA/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 ETA/BR antagonists, which may be effective anti-angiogenic and anti-tumor molecules for the treatment of Kaposi's sarcoma.

Original languageEnglish
Pages (from-to)753-762
Number of pages10
JournalAmerican Journal of Pathology
Volume163
Issue number2
Publication statusPublished - Aug 1 2003

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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