We have therefore screened the serum-free supernatant of simvastatin-treated 518A2 melanoma cells for cytokines. While INF-γ, TNF-α, IL-1α, IL-1β, IL-10 and IL-12 were not regulated by simvastatin, most strikingly, IL-6 levels were significantly decreased. IL-6 is an important prognostic marker in late stage melanoma. Due to this crucial role in the autocrine regulation of the tumour growth this cytokine was investigated in greater detail. A375 and 518A2 melanoma cells were transfected with a fluorescent Stat-3 fusion protein and showed IL-6-mediated translocation of Stat-3-YFP into the nucleus. This was followed by a transient phosphorylation of Stat-3. Conversely, the ''IL-6-insensitive'' melanoma cell lines, WM278 and WM793B, showed constitutively active Stat-3 phosphorylation and virtually no regulation upon IL-6 addition. Interestingly, the latter cells were approximately 10-fold less susceptible toward statin-induced caspase 3 activation compared to A375 and 518A2 melanoma cells. Moreover, addition of IL-6 to simvastatin-treated A375 and 518A2 melanoma cells abrogated the pro-apoptotic effect of statins.