Endogenously synthesized n-3 fatty acids in fat-1 transgenic mice prevent melanoma progression by increasing E-cadherin expression and inhibiting ß-catenin signaling.

Malignant melanoma is the most lethal form of skin cancer. Although preclinical studies have shown that n-3 polyunsaturated fatty acids (PUFAs) are beneficial for prevention of melanoma, the molecular mechanisms underlying the protective effects of n­3 PUFAs on melanoma remain largely unknown. In the present study, endogenously increased levels of n-3 PUFAs in the tumor tissues of omega­3 fatty acid desaturase (fat­1) transgenic mice was associated with a reduction in the growth rate of melanoma xenografts. This reduction in tumor growth in fat­1 mice compared with wild­type controls may have been associated, in part, to the: i) Increased expression of E­cadherin and the reduced expression of its transcriptional repressors, the zinc finger E­box binding homeobox 1 and snail family transcriptional repressor 1; ii) significant repression of the epidermal growth factor receptor/Akt/ß­catenin signaling pathway; and iii) formation of significant levels of n­3 PUFA­derived lipid mediators, particularly resolvin D2 and E1, maresin 1 and 15­hydroxyeicosapentaenoic acid. In addition, vitamin E administration counteracted n­3 PUFA­induced lipid peroxidation and enhanced the antitumor effect of n­3 PUFAs, which suggests that the protective role of n­3 PUFAs against melanoma is not mediated by n­3 PUFAs­induced lipid peroxidation. These results highlight a potential role of n­3 PUFAs supplementation for the chemoprevention of melanoma in high­risk individuals, and as a putative adjuvant agent in the treatment of malignant melanoma.