title: Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53.
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.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: See-Hyoung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Hanyang University School of Medicine, Seoul 133-792, Republic of Korea.
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berek
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mickey C-T
authors.initials: MC
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001310:Auranofin
references.citation: Biochem Pharmacol. 1990 Jan 15;39(2):285-91
references.pmid: 2105731
references.citation: Cell. 2007 Jan 26;128(2):309-23
references.pmid: 17254969
references.citation: Nature. 1994 Sep 22;371(6495):346-7
references.pmid: 8090205
references.citation: Cell. 1999 Mar 19;96(6):857-68
references.pmid: 10102273
references.citation: Cancer Invest. 2009 Jan;27(1):52-9
references.pmid: 19160093
references.citation: Science. 2004 Dec 17;306(5704):2105-8
references.pmid: 15604409
references.citation: Future Oncol. 2005 Feb;1(1):67-78
references.pmid: 16555977
references.citation: Cancer Sci. 2010 Apr;101(4):831-5
references.pmid: 20132225
references.citation: Cell. 2004 Apr 16;117(2):225-37
references.pmid: 15084260
references.citation: Breast Cancer Res Treat. 2011 Aug;129(1):11-21
references.pmid: 21336599
references.citation: Nature. 2007 Aug 9;448(7154):645-6
references.pmid: 17687303
references.citation: Semin Arthritis Rheum. 1987 Aug;17(1):71-80
references.pmid: 3306933
references.citation: Nat Rev Mol Cell Biol. 2013 Feb;14(2):83-97
references.pmid: 23325358
references.citation: Oncogene. 2008 Apr 7;27(16):2312-9
references.pmid: 18391973
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: PLoS One. 2010 Jul 02;5(7):e11171
references.pmid: 20625400
references.citation: Curr Oncol. 2007 Oct;14(5):195-208
references.pmid: 17938703
references.citation: Med Oncol. 2012 Dec;29(5):3409-15
references.pmid: 22714061
references.citation: J Biol Chem. 2003 Dec 12;278(50):49795-805
references.pmid: 14527951
references.citation: Cancer Res. 1998 Nov 15;58(22):5075-8
references.pmid: 9823314
references.citation: Oncogene. 2005 Nov 14;24(50):7410-25
references.pmid: 16288288
references.citation: EMBO Rep. 2013 May;14(5):414-21
references.pmid: 23588418
references.citation: Br J Pharmacol. 2002 Aug;136(8):1162-8
references.pmid: 12163349
references.citation: Cell Death Differ. 1999 Nov;6(11):1028-42
references.pmid: 10578171
references.citation: J Immunol. 2000 Jun 1;164(11):5981-9
references.pmid: 10820281
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):101-12
references.pmid: 18371339
references.citation: Oncol Rep. 2012 Aug;28(2):395-408
references.pmid: 22641286
references.citation: Cell. 2004 Apr 16;117(2):211-23
references.pmid: 15084259
references.citation: Br J Pharmacol. 2005 Oct;146(4):506-13
references.pmid: 16086031
references.citation: Int J Oncol. 2006 Sep;29(3):643-8
references.pmid: 16865280
references.citation: Nat Cell Biol. 2008 Apr;10(4):460-7
references.pmid: 18344987
references.citation: Int J Oncol. 2004 Nov;25(5):1495-500
references.pmid: 15492844
references.citation: Cell Cycle. 2008 Jan 15;7(2):154-7
references.pmid: 18212532
references.citation: Clin Cancer Res. 2013 Mar 1;19(5):961-8
references.pmid: 23307860
references.citation: Antioxid Redox Signal. 2005 May-Jun;7(5-6):752-60
references.pmid: 15890021
references.citation: Inflammopharmacology. 2012 Dec;20(6):297-306
references.pmid: 22965242
references.citation: Nature. 2001 Oct 18;413(6857):744-7
references.pmid: 11607034
references.citation: Science. 2002 Apr 19;296(5567):530-4
references.pmid: 11964479
references.citation: Future Oncol. 2006 Feb;2(1):83-9
references.pmid: 16556075
references.citation: Nat Commun. 2012;3:1000
references.pmid: 22893124
references.citation: Cancer Res. 2006 Jan 1;66(1):212-20
references.pmid: 16397234
references.citation: Br J Pharmacol. 2004 Jun;142(4):749-55
references.pmid: 15159275