Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. Since metastasis of melanoma is the leading cause of death due to skin diseases, an approach that decreases its invasiveness or metastatic ability may facilitate the development of an effective strategy for its treatment and/or prevention. Some drugs has demonstrated potential in treatment of melanoma but their use as chemopreventive agents is questionable due to long-term safety, resistance and toxicity concerns. Dietary bioactive components that have low toxicity are of interest as chemopreventives, including the proanthocyanidins, which do not exhibit gross toxicity in mice. Proanthocyanidins, which are highly enriched in grape seeds, have anti-skin carcinogenic effects in mouse models, but their effects on metastasis have not been explored. We have found that treatment of some metastatic human melanoma cells (A375, Hs294t) with grape seed proanthocyanidins (GSPs) inhibited their migration, as determined using a Boyden chamber assay, suggesting the possibility that GSPs may be effective in inhibiting metastasis. As mutations in b-catenin are one of the most common alterations associated with melanoma development and metastasis and mutated b- catenin is associated with aggressive tumor growth, we examined the effects of the b-catenin status and found that the GSPs-mediated inhibition of melanoma cell invasion was associated with inactivation of b-catenin and that melanoma cells that have activated b-catenin (Mel 1241) showed significantly greater invasion than those melanoma cells that have inactivated b-catenin (Mel 1011). Based on our preliminary data, we have formulated the innovative hypothesis that the inhibition of migration or invasiveness of melanoma cells by GSPs is mediated, at least in part, through inactivation of b-catenin and that is critical for their chemopreventive effects on melanoma metastasis. Our long-term goal is to fully test this hypothesis. The objectives of this exploratory R21 application are o verify and extend our preliminary results using in vitro cell culture and in vivo athymic nude mouse model in order to generate the data necessary for the design of studies that will rigorously test the central hypothesis in mouse model and establish the molecular basis for the observed data. We propose two complementary Specific Aims: (1) To determine whether GSPs inhibit cell invasion of human melanoma cell lines with different mutations, and whether inhibition of cell invasion by GSPs requires inactivation of b-catenin and its signaling. Normal human epidermal melanocytes will serve as a control, and (2) To determine the effect of dietary GSPs on the invasive potential of human melanoma cells in vivo in athymic nude mice, and to ascertain whether the inhibitory effect of GSPs on cell metastasis is associated with inactivation of b-catenin in this model.
These studies will generate knowledge concerning the effects of GSPs on melanoma invasiveness/metastasis in vivo and the mechanism of action that is necessary for future studies of their potential long-term use for suppression of metastatic melanoma.
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