Reactive oxygen species (ROS)-mediated Akt inhibition by genistein induces autophagic cell death in ovarian cancer cells

Abstract

Cancer cells are vulnerable to reactive oxygen species (ROS) due to redox imbalance. Recently, genistein, a polyphenolic compound, has shown to have pro-oxidant activity, causing cell death in several types of malignancies, including breast, prostate and hematologic cancers. Here, we show that in ovarian cancer cells genistein invokes the cell death through autophagy and the generation of ROS. As a matter of fact, genistein increases the level of ROS giving rise to apoptosis and autophagy. In addition, pretreatment with the autophagy inhibitor, 3-methyladenine (3-MA), suppressed genistein-mediated cell death in ovarian cancer cells. These results suggest that autophagy is involved in genistein-mediated cell death. Interestingly, genistein-mediated cell death was restored by ROS scavengers, such as N-acetyl-L-cysteine (NAC) and Trolox, suggesting an essential role of intrinsic ROS in genistein-induced autophagic cell death. Moreover, genistein stimulates the inhibition of the AKT/mTOR signaling pathway through a ROS-mediated mechanism. Taken together, our study suggests that genistein-mediated cell death through inhibition of the AKT/mTOR signaling pathway and ROS-induced autophagy is important for cancer cell killing.