Endothelin-1 decreases basic apoptotic rates in human melanoma cell lines.

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.