Normal human melanocytes respond to
endothelin-1 with induced proliferation and differentiation. Whereas in cultured
melanoma cells the predominant
endothelin receptor, ET(B)-R, is consistently downregulated, ET(B)-R upregulation was recently reported for
melanoma tumors. Contrary to the pro-survival activity described for
endothelin in vascular cells, a proapoptotic activity of
endothelin-1 has been reported for
melanoma cells, in previous studies. We therefore investigated the role of
endothelin for
melanoma cells with respect to apoptosis and proliferation. Treatment with 10 nM
endothelin-1 was a strong mitogenic signal for normal human melanocytes, which responded with a 4-6-fold increase of
thymidine incorporation, whereas the response was only 1.2-fold for SK-Mel-19, the
melanoma cell line characterized by the highest ET(B)-R expression, and it was even less in other cell lines. Determination of the apoptotic rates revealed that
endothelin-1 significantly reduced basic apoptotic rates to 75% both in SK-Mel-19 and in normal melanocytes. After cell synchronization, an antiapoptotic effect of
endothelin-1 was seen in five of seven cell lines investigated. In the cell line Bro, which showed no response and which lacks ET(B)-R expression, responsibility could be restored by overexpression of ET(B)-R after stable transfection, indicating that the effectors of the
endothelin-1 signal cascade were active in these cells, and that the antiapoptotic effect of
endothelin-1 is mediated in a receptor-specific way. This antiapoptotic activity of
endothelin for
melanoma cells combined with upregulation of
endothelin receptors in the
tumor may be a crucial step for
melanoma progression.