Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53

Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel Anticancer therapeutics, we unexpectedly identified auranofin as a potent Anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated Anticancer activity in ovarian Cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose‑ and time‑dependent manner. Auranofin treatment activates the pro-apoptotic Caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular Apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated Apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and Apoptosis in Cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced Apoptosis in ovarian Cancer cells.