Luteolin inhibits proliferation and induces apoptosis of human melanoma cells in vivo and in vitro by suppressing MMP-2 and MMP-9 through the PI3K/AKT pathway

Abstract

Since the incidence rate of malignant melanoma is increasing annually, development of drugs against melanoma cell metastasis has become more urgent. Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake and exhibits a wide spectrum of pharmacological properties. However, the potential anti-cancer role of luteolin in melanoma cells has not been fully investigated. In this study, we have explored whether luteolin inhibits the migration and invasion of A375 human melanoma cells and further elucidated the underlying anti-cancer molecular mechanism of luteolin in melanoma cells. A proliferation assay, flow cytometry and an apoptosis assay were applied to detect the effect of luteolin on the growth and apoptosis of A375 cells. Wound healing assay and transwell invasion assay were used to explore the impact of luteolin on the migration and invasion of A375 cells. Real-time quantitative PCR, western blot and immunofluorescence analysis were used to investigate the effects of luteolin on the expressions of MMP-2, MMP-9 and PI3K/AKT1 in A375 cells. A xenograft tumor animal model was used to investigate the anti-cancer effect of luteolin on the growth of the A375 cells in vivo. Our data indicated that luteolin significantly inhibited the proliferation, migration and invasion of A375 cells and induced the apoptosis of A375 cells in a concentration-dependent manner. Moreover, luteolin reduced the expressions of MMP-2 and MMP-9 and increased the expression of TIMP-1 and TIMP-2. Furthermore, luteolin significantly inhibited the tumor growth of A375 cells in a xenograft mouse model. The immunofluorescence and immunoblotting assays indicated that luteolin inhibited the phosphorylation of AKT1 and PI3K. In conclusion, both in vivo and in vitro studies showed that luteolin inhibited the proliferation and induced the apoptosis of A375 human melanoma cells by reducing the expressions of MMP-2 and MMP-9 through the PI3K/AKT pathway. Overall, luteolin can be considered as a promising anti-cancer agent for the treatment of human melanoma.