Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
October 2014 Volume 45 Issue 4

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
October 2014 Volume 45 Issue 4

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

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
  • View Affiliations / Copyright

    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
  • Pages: 1691-1698
    |
    Published online on: August 4, 2014
       https://doi.org/10.3892/ijo.2014.2579
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



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.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

View References

1 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar

2 

Banerjee S and Kaye SB: New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res. 19:961–968. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Shigetomi H, Higashiura Y, Kajihara H and Kobayashi H: Targeted molecular therapies for ovarian cancer: an update and future perspectives. Oncol Rep. 28:395–408. 2012.PubMed/NCBI

4 

Snyder RM, Mirabelli CK and Crooke SJ: The cellular pharmacology of auranofin. Semin Arthritis Rheum. 17:71–80. 1987. View Article : Google Scholar : PubMed/NCBI

5 

Madeira JM, Gibson DL, Kean WF and Klegeris A: The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology. 20:297–306. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Columbo M, Galeone D, Guidi G, Kagey-Sobotka A, Lichtenstein LM, Pettit GR and Marone G: Modulation of mediator release from human basophils and pulmonary mast cells and macrophages by auranofin. Biochem Pharmacol. 39:285–2891. 1990. View Article : Google Scholar : PubMed/NCBI

7 

Rigobello MP, Scutari G, Boscolo R and Bindoli A: Induction of mitochondrial permeability transition by auranofin, a gold(I)-phosphine derivative. Br J Pharmacol. 136:1162–1168. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Jeon KI, Jeong JY and Jue DM: Thiol-reactive metal compounds inhibit NF-κB activation by blocking IκB kinase. J Immunol. 164:5981–5989. 2000.PubMed/NCBI

9 

Kim IS, Jin JY, Lee IH and Park SJ: Auranofin induces apoptosis and when combined with retinoid acid enhances differentiation of acute promyelocytic leukaemia cells in vitro. Br J Pharmacol. 142:749–755. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Park SJ and Kim IS: The role of p38 MAPK activation for auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells. Br J Pharmacol. 146:506–513. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Tsai WB, Chung YM, Zou Y, Park SH, Xu Z, Nakayama K, Lin SH and Hu MC: Inhibition of FOXO3 tumor suppressor function by βTrCP1 through ubiquitin-mediated degradation in a tumor mouse model. PLoS One. 5:e111712010.

12 

Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R and Hung MC: IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 117:225–237. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Katoh M and Katoh M: Human FOX gene family. Int J Oncol. 25:1495–1500. 2004.PubMed/NCBI

14 

Alvarez B, Martinez AC, Burgering BM and Carrera AC: Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature. 413:744–747. 2001. View Article : Google Scholar : PubMed/NCBI

15 

Furukawa-Hibi Y, Kobayashi Y, Chen C and Motoyama N: FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal. 7:752–760. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI

17 

Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC and Lam EW: FOXO3 transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem. 278:49795–49805. 2003. View Article : Google Scholar : PubMed/NCBI

18 

Fu Z and Tindall DJ: FOXOs, cancer and regulation of apoptosis. Oncogene. 27:2312–2319. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Chung YM, Park SH, Tsai WB, Wang SY, Ikeda MA, Berek JS, Chen DJ and Hu MC: FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage. Nat Commun. 3:10002012. View Article : Google Scholar : PubMed/NCBI

20 

Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW and Greenberg ME: DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 296:530–534. 2002. View Article : Google Scholar : PubMed/NCBI

21 

Tsai WB, Chung YM, Takahashi Y, Xu Z and Hu MC: Functional interaction between FOXO3 and ATM regulates DNA damage response. Nat Cell Biol. 10:460–467. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Yang J-Y, Xia W and Hu MC: Induction of FOXO3a and Bim expression in response to ionizing radiation. Int J Oncol. 29:643–648. 2006.PubMed/NCBI

23 

Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Burgering BM, Coombes RC and Lam EW: Paclitaxel-induced nuclear translocation of FOXO3 in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res. 66:212–220. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Nemoto S, Fergusson MM and Finkel T: Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science. 306:2105–2108. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Seoane J, Le HV, Shen L, Anderson SA and Massagué J: Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 117:211–223. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH and DePinho RA: FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 128:309–323. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama KI, Harada M, Motoyama N, Suda T and Hirao A: FOXO3 is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 1:101–112. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Huang H and Tindall DJ: FOXO factors: a matter of life and death. Future Oncol. 2:83–89. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Hu MC and Hung MC: Role of IkappaB kinase in tumorigenesis. Future Oncol. 1:67–78. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Eijkelenboom A and Burgering BM: FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 14:83–97. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Lu M, Zhao Y, Xu F, Wang Y, Xiang J and Chen D: The expression and prognosis of FOXO3a and Skp2 in human ovarian cancer. Med Oncol. 29:3409–3915. 2012. View Article : Google Scholar : PubMed/NCBI

33 

Fei M, Zhao Y, Wang Y, Lu M, Cheng C, Huang X, Zhang D, Lu J, He S and Shen A: Low expression of Foxo3a is associated with poor prognostic in ovarian cancer patients. Cancer Invest. 27:52–59. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Habashy HO, Rakha EA, Aleskandarany M, Ahmed MA, Green AR, Ellis IO and Powe DG: FOXO3a nuclear localization is associated with good prognosis in luminal-like breast cancer. Breast Cancer Res Treat. 129:11–21. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Nicholson DW: Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6:1028–1042. 1999. View Article : Google Scholar : PubMed/NCBI

36 

Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG and Earnshaw WC: Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 371:346–347. 1994. View Article : Google Scholar : PubMed/NCBI

37 

Kumari SR, Mendoza-Alvarez H and Alvarez-Gonzalez R: Functional interactions of p53 with poly(ADP-ribose) polymerase (PARP) during apoptosis following DNA damage: covalent poly(ADP-ribosyl)ation of p53 by exogenous PARP and noncovalent binding of p53 to the M(r) 85,000 proteolytic fragment. Cancer Res. 58:5075–5078. 1998.

38 

Carvajal LA and Manfredi JJ: Another fork in the road - life or death decisions by the tumour suppressor p53. EMBO Rep. 14:414–421. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Yoshida K and Miki Y: The cell death machinery governed by the p53 tumor suppressor in response to DNA damage. Cancer Sci. 101:831–835. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Das S, Boswell SA, Aaronson SA and Lee SW: P53 promoter selection: choosing between life and death. Cell Cycle. 7:154–157. 2008. View Article : Google Scholar : PubMed/NCBI

41 

Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW and Bryson P: Optimal chemotherapy treatment for women with recurrent ovarian cancer. Curr Oncol. 14:195–208. 2007. View Article : Google Scholar : PubMed/NCBI

42 

Chong CR and Sullivan DJ Jr: New uses for old drugs. Nature. 448:645–646. 2007. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Park S, Lee JH, Berek JS and Hu MC: Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol 45: 1691-1698, 2014.
APA
Park, S., Lee, J.H., Berek, J.S., & Hu, M.C. (2014). Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. International Journal of Oncology, 45, 1691-1698. https://doi.org/10.3892/ijo.2014.2579
MLA
Park, S., Lee, J. H., Berek, J. S., Hu, M. C."Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53". International Journal of Oncology 45.4 (2014): 1691-1698.
Chicago
Park, S., Lee, J. H., Berek, J. S., Hu, M. C."Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53". International Journal of Oncology 45, no. 4 (2014): 1691-1698. https://doi.org/10.3892/ijo.2014.2579
Copy and paste a formatted citation
x
Spandidos Publications style
Park S, Lee JH, Berek JS and Hu MC: Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol 45: 1691-1698, 2014.
APA
Park, S., Lee, J.H., Berek, J.S., & Hu, M.C. (2014). Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. International Journal of Oncology, 45, 1691-1698. https://doi.org/10.3892/ijo.2014.2579
MLA
Park, S., Lee, J. H., Berek, J. S., Hu, M. C."Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53". International Journal of Oncology 45.4 (2014): 1691-1698.
Chicago
Park, S., Lee, J. H., Berek, J. S., Hu, M. C."Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53". International Journal of Oncology 45, no. 4 (2014): 1691-1698. https://doi.org/10.3892/ijo.2014.2579
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team