Abstract
Tumor metastasis is still the leading cause of melanoma mortality. Luteolin, a natural flavonoid, is found in fruits, vegetables, and medicinal herbs. The pharmacological action and mechanism of luteolin on the metastasis of melanoma remain elusive. In this study, we investigated the effect of luteolin on A375 and B16‐F10 cell viability, migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells. Epithelial–mesenchymal transition (EMT) markers and pivotal molecules in HIF‐1α/VEGF signaling expression were analysed using western blot assays or quantitative real‐time polymerase chain reaction. Results showed that luteolin inhibits cellular proliferation in A375 and B16‐F10 melanoma cells in a time‐dependent and concentration‐dependent manner. Luteolin significantly inhibited the migratory, invasive, adhesive, and tube‐forming potential of highly metastatic A375 and B16‐F10 melanoma cells or human umbilical vein endothelial cells at sub‐IC50 concentrations, where no significant cytotoxicity was observed. Luteolin effectively suppressed EMT by increased E‐cadherin and decreased N‐cadherin and vimentin expression both in mRNA and protein levels. Further, luteolin exerted its anti‐metastasis activity through decreasing the p‐Akt, HIF‐1α, VEGF‐A, p‐VEGFR‐2, MMP‐2, and MMP‐9 proteins expression. Overall, our findings first time suggests that HIF‐1α/VEGF signaling‐mediated EMT and angiogenesis is critically involved in anti‐metastasis effect of luteolin as a potential therapeutic candidate for melanoma.
Highlights
(Becker et al, 2017)
We performed MTT assay to evaluate the inhibitory effects of luteolin on the proliferation of A375 and B16‐F10 cells
The results demonstrated that luteolin significantly inhibited the proliferation of A375 and B16‐F10 cells in a time‐dependent and dose‐dependent manner
Summary
(Becker et al, 2017). the exploration of therapeutic candidate for melanoma metastasis is very attractive to cancer research. HIF‐1α expression profile was correlated with the expression levels of E‐cadherin, N‐cadherin, and vimentin (Lai et al, 2016) Based on these findings, HIF‐1α/VEGF signal pathway is considered to be an important target for the treatment of angiogenesis‐related diseases including metastasis of cancer. Luteolin effectively blocked progestin‐dependent angiogenesis and the stem cell‐like phenotype in human breast cancer cells (Cook, 2018). These studies revealed luteolin's protective roles in cancer, the effects and underlying mechanisms of luteolin on the metastasis of melanoma have not been reported previously. In the present study, we evaluated the effects of luteolin on A375 and B16‐F10 cell viability, migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). The underlying molecular mechanism of luteolin anti‐metastasis were investigated in association with inhibition of HIF‐1α/VEGF signaling pathway and the resulting decreased EMT and angiogenesis
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