Breast cancer suppression by aplysin is associated with inhibition of PI3K/AKT/FOXO3a pathway

Aplysin, a bromosesquiterpene isolated from Aplysia kurodai, was explored as a potential anti-breast cancer agent by us. However, the mechanisms underlying the anticarcinogenic effect of aplysin remain unclear. Here, aplysin was found to remarkably suppress tumor growth in vivo, inhibit cell proliferation and promote apoptosis in vitro. Additionally, we demonstrated that aplysin attained these effects in part by down-regulating PI3K/AKT/FOXO3a signaling pathway. Aplysin treatment inhibited the phosphorylation levels of AKT (Ser-473) and AKT-dependent phosphorylation of FOXO3a (Ser-253) in breast cancer cell lines and breast cancer tissues. The expression levels of FOXO3a-targeted genes were also destabilized by aplysin, cyclin D1 and Bcl-XL were declined; however, p21(CIP1), p27(KIP1), Bim, TRAIL and FasL were increased both in vivo and in vitro. Furthermore, activation of the PI3K/AKT signaling pathway by an activator and silencing of FOXO3a by shRNA protected the cells from aplysin mediated growth suppression and apoptosis. In summary, our findings revealed that aplysin could suppress breast cancer progression by inhibiting PI3K/AKT/FOXO3a pathway, thereby suggesting a potential role of aplysin as a chemoprevention drug for patients with breast cancer.