Abstract
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, p21CIP1, p27KIP1, 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.
Highlights
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide [1]
To test the possibility that aplysin preventive treatment would suppress breast tumor growth, female Wistar rats with mammary gland tumor induced by DMBA were fed 0, 20, 40 and 80 mg/kg aplysin each day respectively for 16 weeks, and tumor growth was periodically recorded. 8 weeks after DMBA injection, rats of Cancer Control group presented at least 1 tumor (80%). weeks later, all of them (100%) developed tumors
The results showed that oral gavage of 40 and 80 mg/kg aplysin significantly reduced the tumor growth
Summary
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide [1]. PI3K/AKT signalling pathway plays a major role in tumor development and in the tumor’s potential response to cancer treatment [6]. FOXO3a, a member of the Forkhead box O (FoxO) transcription factor family, functions downstream of PI3K/AKT pathway and acts as a tumor suppressor in the majority of human cancers [7, 8]. Chemotherapeutic drugs paclitaxel and KP372−1, which are currently used in the treatment of breast carcinoma and acutemyeloid leukemia, can activate FOXO3a by reducing AKT activity [9, 10]; gene-targeted drugs such as trastuzumab and cetuximab enhance the drug sensitivity of drug-resistant tumor cells by activating FOXO3a activity and causing overexpression of FOXO3a responsive genes such as Bim, p21CIP1 and p27KIP1 [8, 11, 12]. Increasing FOXO3a activity has become an important cancer therapeutic strate
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