The expression and signaling of the vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) alpha, delta, gamma was investigated in the melanoma cell line MeWo. Using real-time PCR, the mRNA of the nuclear receptors (NR) was detected. The strongest expression was found for the VDR, approximately 3-fold higher compared to the expression of PPARalpha or PPARdelta, and the weakest expression was for PPARgamma. After treatment with corresponding ligands, the expression of the VDR, PPARalpha and PPARdelta was elevated up to 5-fold, while the PPARgamma expression was not significantly affected. Treatment with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitrol) resulted in 40% inhibition of MeWo cell proliferation, that was associated with a 5-fold increase in VDR mRNA. Interestingly, cell proliferation was differentially modulated by treatment with the PPAR ligands. While docosahexaenoic acid (DHA) treatment resulted in a statistically significant increase (approximately 10%), the other PPAR ligands inhibited MeWo cell proliferation. GW501516 (PPARdelta ligand) and WY14643 (PPARalpha ligand) both had an antiproliferative effect of approximately 10%. These antiproliferative effects were not associated with modulation of PPARalpha or PPARdelta expression. In contrast, stimulation of MeWo proliferation by DHA was associated with a 3- and 4-fold increase in the expression of PPARalpha and PPARdelta, respectively. Analyzing the cross-talk between the VDR and PPAR signaling pathways, the 1,25(OH)2D3 treatment resulted in an approximately 2-fold increase in expression of PPARalpha and PPARdelta, while the expression of PPARgamma was unaffected. Treatment with GW501516 and WY14643 resulted in an increase in the VDR expression (2-fold after 120 h). The simultaneous treatment with 1,25(OH)2D3 partially antagonised the DHA- and alpha-linolenicacid (ALA)-induced up-regulation of PPAR expression. In contrast, treatment with the PPAR ligands had no pronounced effect on the 1,25(OH)2D3-induced increase in VDR expression. Simultaneous treatment with the PPAR ligands bezafibrate or ALA resulted in an up to 6-fold reduction of the 1,25(OH)2D3-induced elevation of the 1alpha,25-dihydroxyvitamin D3-24-hydroxylase (CYP24A1) expression. Simultaneous treatment with the PPAR ligands and 1,25(OH)2D3 resulted in only marginal modulation of 1,25(OH)2D3-induced inhibition of cell proliferation. However, simultaneous treatment with bezafibrate and 1,25(OH)2D3 resulted in a statistically significant partial antagonisation of the 1,25(OH)2D3-induced inhibition of MeWo cell proliferation. In conclusion, PPAR and VDR have a role in growth regulation in melanoma cells and functionally relevant cross-talk between these nuclear signaling pathways is indicated, but not at the level of cell proliferation, where 1,25(OH)2D3 has a dominant effect.