Cancer letters
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The anti-tumor activity of rapamycin is compromised by the feedback-loop-relevant hyperactive PI3K and ERK-MAPK pathway signaling. In breast cancer cells treated with rapamycin, we observed a moderate increase of AKT phosphorylation (P-AKT) in a rapamycin resistant cell line, MDA-MB-231, as well as a slight increase of P-AKT in a rapamycin sensitive cell line, MCF-7. We found that resveratrol, a natural phytoalexin, suppressed the phosphorylation and activation of the PI3K/AKT pathway in all the three breast cancer cell lines that we tested. ⋯ We, therefore, reveal a novel combination whereby resveratrol potentiates the growth inhibitory effect of rapamycin, with the added benefit of preventing eventual resistance to rapamycin, likely by suppressing AKT signaling. We also present data herein that PTEN is an important contributor to resveratrol's growth suppressive effects and its potentiation of rapamycin in this therapeutic scenario, as resveratrol's suppression of rapamycin-mediated induction of P-AKT is both PTEN-dependent and -independent. Thus, the resveratrol-rapamycin combination may have therapeutic value in treating breast cancer and perhaps other processes where mTOR is activated.