Abstract
Melanoma is highly resistant to chemotherapy, and the mortality rate is increasing rapidly worldwide. STAT3 signaling has been implicated in the pathogenesis of melanoma and constitutive activated STAT3 has been validated can as a target for melanoma therapy. Quercetin, a noncarcinogenic dietary flavonoid with low toxicity, has been shown to exert anti-melanoma activity. However, the anti-melanoma mechanisms of quercetin are not fully understood. In this study, we sought to test the involvement of STAT3 signaling in the inhibitory effects of quercetin on melanoma cell growth, migration and invasion. Our results showed that exposure to quercetin resulted in inhibition of proliferation of melanoma cells, induction of cell apoptosis, and suppression of migratory and invasive properties. Mechanistic study indicated that quercetin inhibited the activation of STAT3 signaling by interfering with STAT3 phosphorylation, and reducing STAT3 nuclear localization. This inhibited STAT3 transcription activity and down-regulated STAT3 targeted genes Mcl-1, MMP-2, MMP-9 and VEGF, which are involved in cell growth, migration and invasion. Importantly, overexpression of constitutively active STAT3 partially rescued the growth inhibiting effects induced by quercetin. Furthermore, quercetin suppressed A375 tumor growth and STAT3 activities in xenografted mice model, and inhibited murine B16F10 cells lung metastasis in an animal model. Overall, these results indicate that the antitumor activity of quercetin is at least partially due to inhibition of STAT3 signaling in melanoma cells. Our findings provided new insight into the action of quercetin potently inhibits the STAT3 signaling pathway, suggesting it has a potential role in the prevention and treatment of melanoma.
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