Potentiation of tumor formation by topical administration of 15-deoxy-Δ12,14-prostaglandin J2 in a model of skin carcinogenesis

The effect of prostaglandins on the development of papillomas has been investigated in mice receiving prostaglandins E-2 (PGE(2)) or the cyclopentenone 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)) topically, using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced tetradecanoylphorbol acetate (TPA)-promoted model of skin carcinogenesis. The presence of 15dPGJ(2) during DMBA and TPA treatment inhibited apoptosis and increased the rate, number, size and vascularization of the papillomas, some of them progressing into carcinomas. Moreover, skin sections from mice treated for one week with DMBA and 15dPGJ(2) showed a much reduced rate of apoptotic cells, and an enhanced expression of vascular epithelial growth factor when compared with animals receiving DMBA, with or without PGE(2). The analysis of molecular events in the MCA3D keratinocyte cell line showed that 15dPGJ(2) activated Ras and improved cell viability by inhibiting DMBA-dependent apoptosis. In addition to this, cell adhesion was impaired in MCA3D keratinocytes co-treated with 15dPGJ(2) and DMBA, at the same time when the expression of cyclooxygenase-2 (COX-2) was observed under these conditions. These effects mediated by 15dPGJ(2) might contribute to understand the role of COX-2 metabolites in carcinogenesis, leading to an increase of cell viability after mutagenic injury and therefore in the progression of tumors.