Resveratrol downregulates acetyl-CoA carboxylase alpha and fatty acid synthase by activating AMP-activated protein kinase and suppressing the mammalian target of rapamycin signal pathway

Expression of HER2 is reported to be increased in approximately 30% of human breast carcinoma. Fatty acid synthase (FASN) was expressed higher in HER2-overexpressing breast cancer cells. Resveratrol (3,5,4'-trihydroxystilbene), a red-wine-derived polyphenol, has been shown to suppress cancer cell proliferation, and to interfere with the several signaling pathways and induce apoptosis. We investigated the effects of resveratrol on the expression of lipogenic enzymes in BT-474 cells, in which HER2 overexpresses cells. Resveratrol treatment to BT-474 cells resulted in inhibition of acetyl-CoA carboxylase alpha (ACCalpha) and FASN expression and a strong activation of AMP-activated protein kinase (AMPK), which could be mimicked by the changes caused by AICAR treatment or forced expression of constitutively active AMPK mutant. The decreased ACCalpha and FASN expressions by resveratrol were abolished by overexpression of dominant-negative AMPK mutant. The activation of AMPK was accompanied with the reduction of the mammalian target of rapamycin (mTOR), which plays a key role in the upregulation of ACCalpha and FASN expression in BT-474 cells. These results indicate that downregulation of HER2-mediated ACCalpha and FASN expression by resveratrol is regulated through suppressing the mTOR signaling pathway resulting from the activation of AMPK in breast cancer cells.