ROS-mediated SIRT2 activation by genistein induces pro-survival autophagy in cisplatin resistant ovarian cancer cells

Abstract

The most serious problem of ovarian cancer is chemoresistance. Autophagy is one of the phenotype contributing to chemoresistance and also has the bidirectional effect during chemotherapy. In this study, we demonstrated that ROS-induced autophagy by genistein has opposing functions regarding chemoresistance in ovarian cancer cell line A2780/CP (cisplatin resistant) and A2780/S (cisplatin sensitive). Genistein induced cell death through ROS generation. Interestingly, with ROS scavenging, the cell death rate was increased in A2780/CP in contrast to decrease in A2780/S. Genistein increased autophagy in both cell lines and the addition of autophagy inhibitor, 3MA, showed the same pattern of cell death rate as that of ROS scavenging. It means that the function of autophagy by genistein was different, pro-survival in A2780/CP while pro-death in A2780/S. SIRT2 promotes autophagy as a defense against the oxidative stress. AGK2, SIRT2 inhibitor, similarly inhibited cell viabilities in both cell lines. Moreover, AGK2 inhibited pro-survival autophagy in A2780/CP and overcame the cisplatin resistance with genistein. Taken together, understanding the autophagy could help to develop the therapeutic design to overcome the chemoresistance in ovarian cancer.