Mammalian target of rapamycin (mTOR) inhibitors are currently under clinical trials as anti-cancer agents. Naturally occurring phytochemical onion quercetin has been evaluated as a potential mTOR inhibitor. In this study, we show that inhibition of mTOR signaling by quercetin leads to apotosis in MCF-7 breast cancer cells. Also the inhibition of mTOR with quercetin was linked to the activation of AMPK. We investigated the feedback from activated AMPK with quercetin on mTOR by treating cancer cells with AMPK inhibitor Compound C. It was found that by abolishing AMPK activities, the inhibitory effect of quercetin on mTOR was decreased. These results suggest that quercetin mediates mTOR suppression through the activation of AMPK. Thus, targeting AMPK/mTOR pathway with flavonoids such as quercetin may be an appropriate strategy to enhance mTOR-targeted anticancer therapy. The activation of AMPK by quercetin appeared to be necessary in the regulation of mTOR in MCF-7 breast cancer cells. The modulation of AMPK-mTOR pathway may emerge as the promising target of flavonoids in controlling breast cancers. (Cancer Prev Res 15, 320-325, 2010)

Keywords: Quercetin, AMP-activated protein kinase, mTOR, MCF-7 cells, Apoptosis