Abstract / Summary
Abstract Purpose Cutaneous melanoma (CM) is the most aggressive form of skin cancer, with a steadily rising incidence worldwide. Hormone-related therapies, particularly those targeting estrogen signaling pathways, have emerged as promising strategies for CM treatment. Cirsimaritin, a flavonoid with reported antitumor activity, has demonstrated efficacy against several cancer types; however, its effects on CM and the involvement of the G-protein–coupled estrogen receptor (GPER) in its action remain unclear. Methods We investigated the anti-melanoma effects of cirsimaritin in A375 and MeWo CM cell lines. Cell viability was evaluated using the MTT assay, apoptosis and cell-cycle distribution were analyzed by flow cytometry, and cell migration by transwell assay. GPER expression and the modulation of key signaling proteins were examined by immunofluorescence staining and Western blotting. Results Cirsimaritin markedly reduced cell viability to 41.1% in A375 cells and 26.1% in MeWo cells, and significantly inhibited migration in both cell lines. It increased apoptotic cell populations to 3.6% in A375 and 8% in MeWo cells and induced cell-cycle arrest at the S and G2/M phases. Immunofluorescence and Western blot analyses confirmed GPER expression in both melanoma cell lines and showed that cirsimaritin down regulated GPER immunofluorescence but upregulated its expression in Western blot analysis. Moreover, cirsimaritin increased P-ERK and c-Myc levels in both cell lines, while decreasing P-Akt expression in MeWo cells without affecting A375 cells. Notably, the GPER antagonist G15 abolished many of the effects of cirsimaritin, suggesting a GPER-associated signaling. Conclusion These findings demonstrate that cirsimaritin exerts antitumor effects in CM cell lines, at least in part, through GPER activation, highlighting its potential as a novel therapeutic candidate for cutaneous melanoma.