Abstract
Melanoma is the most serious type of skin disease and a leading cause of death from skin disease due to its highly metastatic ability. To develop more effective chemopreventive agents for the prevention of melanoma, we have determined the effect of green tea catechins on the invasive potential of human melanoma cells and the molecular mechanisms underlying these effects using A375 (BRAF-mutated) and Hs294t (Non-BRAF-mutated) melanoma cell lines as an in vitro model. Employing cell invasion assays, we found that the inhibitory effects of green tea catechins on the cell migration were in the order of (-)-epigallocatechin-3-gallate (EGCG)>(-)-epigallocatechin>(-)-epicatechin-3-gallate>(-)-gallocatechin>(-)-epicatechin. Treatment of A375 and Hs294t cells with EGCG resulted in a dose-dependent inhibition of cell migration or invasion of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2, prostaglandin (PG) E2 and PGE2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, also inhibited melanoma cell migration. EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate-, an inducer of COX-2, and PGE2-induced cell migration of cells. EGCG decreased EP2 agonist (butaprost)- and EP4 agonist (Cay10580)-induced cell migration ability. Moreover, EGCG inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A375 melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited cell migration. Inhibition of melanoma cell migration by EGCG was associated with transition of mesenchymal stage to epithelial stage, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin, cytokeratin and desmoglein 2) and a reduction in the levels of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in A375 melanoma cells. Together, these results indicate that EGCG, a major green tea catechin, has the ability to inhibit melanoma cell invasion/migration, an essential step of metastasis, by targeting the endogenous expression of COX-2, PGE2 receptors and epithelial-to-mesenchymal transition.
Highlights
The melanoma remains the leading cause of death from skin diseases due to its propensity to metastasis
These results suggest that the cell migration ability of BRAF-mutated A375 cells was higher than non-BRAF-mutated Hs294t cells; the difference was not statistically significant
This screening preliminary experiment revealed that EGCG has greater inhibitory effect on melanoma cell migration compared to other tea catechins; EGCG was selected for further studies of cell invasion behavior of human melanoma cells and the molecular mechanisms underlying these effects
Summary
The melanoma remains the leading cause of death from skin diseases due to its propensity to metastasis. If recognized and treated early, melanoma is curable, but as the disease progresses its propensity to metastasize make it difficult to treat. Chronic exposure to solar ultraviolet (UV) radiation has been implicated in melanoma and non-melanoma skin cancers [4,5]. The enhanced generation of PGs, PGE2, plays a central role in orchestrating the multiple events involved in cancer invasion and metastasis. Melanoma is a highly malignant cancer with a potent capacity to metastasize distantly, an approach that reduces its metastatic ability may facilitate the development of an effective strategy for its treatment and/or prevention
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