Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 45, Issue 4, Pages 1691-1698Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2014.2579
Keywords
auranofin; cancer; FOXO; Forkhead; apoptosis; caspase; Bax; Bim; p53; I kappa B kinase; tumor suppression
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Funding
- National Cancer Institute, National Institutes of Health [CA113859]
- Stanford Cancer Institute
- Avon Foundation for Women [02-2013-051]
- Ann Schreiber Research Award from the Ovarian Cancer Research Fund
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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.
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