Resveratrol-induced growth inhibition in MDA-MB-231 breast cancer cells is associated with mitogen-activated protein kinase signaling and protein translation

Resveratrol (3,4',5-trans-trihydroxystilbene) is a natural compound found in grapes and several medicinal plants and has been shown to have anticancer effects on various human cancer cells. The aim of this study was to further investigate the molecular mechanism of this anticancer effect. Resveratrol effect on cell growth, morphology and gene expression was investigated in estrogen receptor-negative MDA-MB-231 human breast cancer cell line. We show here that resveratrol-induced growth inhibition in the estrogen receptor negative MDA-MB-231 breast cancer cells is due to the induction of apoptosis as demonstrated by morphological, nuclear staining and PARP cleavage analysis. Resveratrol-induced growth inhibition was associated with transient activation of p44/42 mitogen-activated protein kinase (MAPK) (Thr202/Tyr204). Most importantly, resveratrol inhibited both the phosphorylation at Ser240/244 and the expression of the pS6 ribosomal protein. This protein is known to play an important role in the translation of mRNAs that have oligopyrimidine tracts in their 5' untranslated regions. Interestingly, only MAPK inhibitor was able to block resveratrol-induced growth inhibition suggesting that effects of resveratrol on cell growth are dependent on MAPK signaling. The data demonstrated that resveratrol-induced apoptosis is associated with MAPK signaling and with the inhibition of proteins that are involved in protein translation. This is the first data linking resveratrol with downregulation of protein translation via p44/42 MAPK and S6 ribosomal protein. We propose to use these proteins as predictive biomarkers to evaluate the treatment efficacy of resveratrol in estrogen receptor-negative human breast cancer.