Ampelopsin suppresses breast carcinogenesis by inhibiting the mTOR signalling pathway

Abstract

The mammalian target of rapamycin (mTOR), which is a master regulator of cellular catabolism and anabolism, plays an important role in tumourigenesis and progression. In this study, we report the chemopreventive effect of the dietary compound ampelopsin (AMP) on breast carcinogenesis in vivo and in vitro, which acts by inhibiting the mTOR signalling pathway. Our study indicates that AMP treatment effectively suppresses 1-methyl-1-nitrosourea (MNU)-induced breast carcinogenesis in rats and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P)-induced cellular carcinogenesis. Additionally, AMP inhibits the growth of breast cancer cells in vitro and in vivo. The activity of mTOR kinase was found to be significantly increased in a time-dependent manner during chronic breast carcinogenesis, and this increase can be suppressed by AMP co-treatment. AMP also effectively suppresses mTOR activity in breast cancer MDA-MB-231 cells. We also demonstrated that AMP is an effective mTOR inhibitor that binds to one site on the mTOR target in two ways. Further studies confirmed that AMP inhibits the activation of Akt, suppresses the formation of mTOR complexes (mTORC)1/2 by dissociating regulatory-associated protein of mTOR and rapamycin-insensitive companion of mTOR and, consequently, decreases the activation of the downstream targets of mTOR, including ribosomal p70-S6 kinase, ribosomal protein S6, eukaryotic translation initiation factor 4B and eukaryotic translation initiation factor 4E-binding protein 1. These finding suggest that AMP is a bioactive natural chemopreventive agent against breast carcinogenesis and is an effective mTOR inhibitor that may be developed as a useful chemotherapeutic agent in the treatment of breast cancer.