Advanced malignant melanoma (MM) is an aggressive malignancy with poor 5-year survival for advanced stage disease. Therapies in addition to surgery and radiation have principally focused on vaccine therapies, because of the immune stimulatory potential of this malignancy. Differentiation therapies have not been intensely investigated as an option for this malignancy. PPAR-gamma activation is one potential path for promoting tumor cell differentiation. Presently, we examined the effects of the PPAR-gamma activators ETYA, PGJ-2, and Pioglitizone in A375 and A2058 melanoma cell lines. MTT assays and cell counts were used to assess proliferation. Lipid differentiation was studied using Oil Red O (ORO) staining and adipophilin induction. We observed dose dependent reductions of >50 % in cell counts and >50 % in MTT assay. Each PPAR-gamma agonist caused lipid droplet formation which was accompanied by was induction of Adipophilin staining on fluorescence IHC. In summary, this treatment demonstrates antiproliferative and transdifferentiation events in MM, in vitro. Induction of adipophilin, a highly specific marker of lipid droplet formation, in malignant melanoma as a result of PPAR-gamma agonism is a novel finding and supports a powerful differentiation effect. The potential of non-toxic small-molecule therapy against MM as an active treatment or chemoprevention role is implied and warrants further study. We conclude that PPAR-gamma activation has antiproliferative effects in MM cell lines. Lipid differentiation occurs with PPAR-gamma agonists and adipophilin induction occurs, suggesting transdifferentiation and anticancer potential.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]