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

Park,See-Hyoung; Lee,Jung  Han; Berek,Jonathan  S.; Hu,Mickey  C.-T.

doi:10.3892/ijo.2014.2579

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

Authors:
- See-Hyoung Park
- Jung Han Lee
- Jonathan S. Berek
- Mickey C.-T. Hu
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Affiliations: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA, Department of Obstetrics and Gynecology, Hanyang University School of Medicine, Seoul 133-792, Republic of Korea
Published online on: August 4, 2014 https://doi.org/10.3892/ijo.2014.2579
Pages: 1691-1698

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Abstract

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.

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