Antitumor Effects of Quercetin and Luteolin in MeWo Melanoma Cells: Potential Association with GPER Signaling

Abstract Introduction with high mortality rate, cutaneous melanoma (CM) is considered the most dangerous form of skin cancer, with steadily increasing incidence worldwide. Hormone-related therapies, especially those involving estrogen (E2), have emerged as promising strategies for treating CM. The phytoestrogens quercetin and luteolin have gained attention due to their antitumor effects across various cancers, including melanoma. However, the precise mechanisms by which they exert their effects and their association with G-protein-coupled estrogen receptor (GPER) signaling in melanoma remain unclear. Methods we investigated the inhibitory effects of quercetin and luteolin in the MeWo melanoma cell line and their modulation of GPER-associated signaling. The effects of the flavonoids on cell viability, apoptosis and cell cycle were examined by MTT assay and flow cytometry. Cell migration was evaluated by transwell assay. GPER expression was verified by immunofluorescence staining, and the impact of the flavonoids on key signaling proteins was confirmed by Western blot. Results we showed that quercetin and luteolin exerted anti-proliferative and anti-migratory effects in melanoma cells. The two flavonoids also induced apoptosis and arrested the cell cycle at S and G2/M phases. Immunofluorescence and immunoblotting confirmed the presence of GPER in this cell line, and treatment with quercetin and luteolin, particularly at 100 µM, upregulated its expression. Quercetin and luteolin, as well as the GPER agonist G-1, enhanced the expression of P-ERK and c-Myc but reduced the expression of P-Akt. These responses were attenuated or reversed by the specific GPER antagonist G15, supporting a potential association between these effects and GPER signaling. Conclusion quercetin and luteolin have antitumor effects on the MeWo melanoma cell line in association with GPER signaling, suggesting that GPER-associated pathways are associated with their anti-melanoma effects and warrant further investigation.