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

作者：Park See Hyoung; Lee Jung Han; Berek Jonathan S; Hu Mickey C T^*

来源：International Journal of Oncology, 2014, 45(4): 1691-1698.

DOI：10.3892/ijo.2014.2579

• auranofin
• cancer
• FOXO
• Forkhead
• apoptosis
• caspase
• Bax
• Bim
• p53
• I kappa B kinase
• tumor suppression

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 I kappa B kinase (IKK)-beta 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.

• 出版日期2014-10