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(American Journal of Pathology. 2001;158:841-847.)
© 2001 American Society for Investigative Pathology

Short Communications

Endothelin Receptor Blockade Inhibits Proliferation of Kaposi’s Sarcoma Cells

Anna Bagnato^*, Laura Rosanò^*, Valeriana Di Castro^*, Adriana Albini, Debora Salani^*, Marco Varmi^*, Maria Rita Nicotra and Pier Giorgio Natali^§

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

Endothelin-1 (ET-1) has been shown to be mitogenic for endothelial and several tumor cells through an autocrine mechanism. In this study we evaluated whether the tumorigenic KS IMM cell line deriving from Kaposi’s sarcoma (KS), a highly angiogenic tumor, is susceptible to ET-1 mitogenic activity. By reverse transcriptase-polymerase chain reaction, we detected ET-1 mRNA expression and both ET_A receptor (ET_AR) and ET_BR mRNA transcripts in the KS IMM cells. High concentrations of ET-1 are released from the KS IMM cells and competition-binding studies demonstrated that these cells also express functional ET_AR and ET_BR with high affinity for ET-1 and ET-1/ET-3, respectively. Expression of ET-1 and cognate receptors could be detected by immunohistochemical method in vitro, in KS IMM xenograft, and in tissue sections of a human KS lesion. Furthermore ET-1 induces a marked and dose-dependent increase in [³H]thymidine incorporation comparable to that elicited by vascular endothelial growth factor. Addition of both selective ET_BR antagonist (BQ 788) and ET_AR antagonist (BQ 123), completely blocked ET-1-induced mitogenic response and reduced the basal growth rate of unstimulated cells, suggesting that both receptors mediated the proliferative signal. Such findings demonstrate that ET-1 participates on KS pathogenesis acting as an autocrine growth factor and that ET-1 receptor antagonists may thus be novel candidates for therapeutic intervention.

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