α-mangostin, a xanthone from <i>garcinia mangostana</i> fruit inhibits MEK1 kinase in prostate cancer

Prostate cancer is the second most common malignancy in men in the United States. Although second-generation anti-androgens are initially effective, eventually drug resistance develops. Hyperactivation of MEK1, a central gatekeeper protein in MAPK pathway, is observed in prostate cancer. Recently, targeting MEK1 has been a fascinating area of research. Here, our data reports that mangosteen xanthones can inhibit MEK1 kinase using a cell-free biochemical assay. Among nine xanthones, γ-mangostin and α-mangostin were most potent, and the presence of an isoprenyl group at position 8 was the key structural difference that can contribute to MEK1 inhibition. Furthermore, α-mangostin dose-dependently inhibited the p-MEK1/2(Ser217/221) and downstream target p-MSK1(Thr581) in both 22Rv1 and PC3 prostate cancer cells. The molecular docking result aligned with our findings of the inhibition assay showing a strong correlation. Taken together, the results suggest that xanthones can directly target MEK1, providing a possible opportunity for their therapeutic potential in prostate cancer.