Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Iron addiction: a novel therapeutic target in ovarian cancer

Oncogene volume 36, pages 4089–4099 (2017)Cite this article

Subjects

Abstract

Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). We show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. A snapshot of ovarian cancer. National Cancer Institute. Available from http://www.cancer.gov/research/progress/snapshots/ovarian (accessed 21 December 2015).

  2. Vang R, Shih IeM, Kurman RJ . Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 2009; 16: 267–282.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Leong HS, Galletta L, Etemadmoghadam D, George J, Kobel M, Ramus SJ et al. Efficient molecular subtype classification of high-grade serous ovarian cancer. J Pathol 2015; 236: 272–277.

    Article  CAS  PubMed  Google Scholar 

  4. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008; 14: 5198–5208.

    Article  CAS  PubMed  Google Scholar 

  5. Lengyel E . Ovarian cancer development and metastasis. Am J Pathol 2010; 177: 1053–1064.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Landen Jr CN, Goodman B, Katre AA, Steg AD, Nick AM, Stone RL et al. Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 2010; 9: 3186–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 2011; 71: 3991–4001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Karst AM, Drapkin R . Ovarian cancer pathogenesis: a model in evolution. J Oncol 2010; 2010: 932371.

    Article  PubMed  Google Scholar 

  9. Ng A, Barker N . Ovary and fimbrial stem cells: biology, niche and cancer origins. Nat Rev Mol Cell Biol 2015; 16: 625–638.

    Article  CAS  PubMed  Google Scholar 

  10. Yamamoto Y, Ning G, Howitt BE, Mehra K, Wu L, Wang X et al. In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells. J Pathol 2016; 238: 519–530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Torti SV, Torti FM . Iron and cancer: more ore to be mined. Nat Rev Cancer 2013; 13: 342–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Torti SV, Torti FM . Ironing out cancer. Cancer Res 2011; 71: 1511–1514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dolma S, Lessnick SL, Hahn WC, Stockwell BR . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003; 3: 285–296.

    Article  CAS  PubMed  Google Scholar 

  14. Li HX, Lu ZH, Shen K, Cheng WJ, Malpica A, Zhang J et al. Advances in serous tubal intraepithelial carcinoma: correlation with high grade serous carcinoma and ovarian carcinogenesis. Int J Clin Exp Pathol 2014; 7: 848–857.

    PubMed  PubMed Central  Google Scholar 

  15. Kurman RJ . Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol 2013; 24 (Suppl 10): x16–x21.

    Article  PubMed  Google Scholar 

  16. Dietl J . Revisiting the pathogenesis of ovarian cancer: the central role of the fallopian tube. Arch Gynecol Obstet 2014; 289: 241–246.

    Article  PubMed  Google Scholar 

  17. Wang W, Deng Z, Hatcher H, Miller LD, Di X, Tesfay L et al. IRP2 regulates breast tumor growth. Cancer Res 2014; 74: 497–507.

    Article  PubMed  Google Scholar 

  18. Gershenson DM . The life and times of low-grade serous carcinoma of the ovary. Am Soc Clin Oncol Educ Book 2013. e195–e199.

    Article  Google Scholar 

  19. Torti FM, Torti SV . Regulation of ferritin genes and protein. Blood 2002; 99: 3505–3516.

    Article  CAS  PubMed  Google Scholar 

  20. Baba T, Convery PA, Matsumura N, Whitaker RS, Kondoh E, Perry T et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 2009; 28: 209–218.

    Article  CAS  PubMed  Google Scholar 

  21. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 2009; 27: 2059–2068.

    Article  CAS  PubMed  Google Scholar 

  22. Ning G, Bijron JG, Yamamoto Y, Wang X, Howitt BE, Herfs M et al. The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium. J Pathol 2014; 234: 478–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Baker VV, Borst MP, Dixon D, Hatch KD, Shingleton HM, Miller D . c-myc amplification in ovarian cancer. Gynecol Oncol 1990; 38: 340–342.

    Article  CAS  PubMed  Google Scholar 

  24. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol 2010; 221: 49–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Manz DH, Blanchette N, Paul B, Torti FM, Torti SV . Iron and Cancer: recent insights. Ann NY Acad Sci 2016; 1368: 149–161.

    Article  CAS  PubMed  Google Scholar 

  26. Domcke S, Sinha R, Levine DA, Sander C, Schultz N . Evaluating cell lines as tumour models by comparison of genomic profiles. Nat commun 2013; 4: 2126.

    Article  PubMed  Google Scholar 

  27. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood 2005; 105: 4096–4102.

    Article  CAS  PubMed  Google Scholar 

  28. Liu XB, Yang F, Haile DJ . Functional consequences of ferroportin 1 mutations. Blood cells mol dis 2005; 35: 33–46.

    Article  CAS  PubMed  Google Scholar 

  29. Bast Jr RC, Hennessy B, Mills GB . The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009; 9: 415–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Coward J, Kulbe H, Chakravarty P, Leader D, Vassileva V . Leinster DA, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res 2011; 17: 6083–6096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dixon SJ, Stockwell BR . The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014; 10: 9–17.

    Article  CAS  PubMed  Google Scholar 

  33. Karst AM, Levanon K, Drapkin R . Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci USA 2011; 108: 7547–7552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miller LD, Coffman LG, Chou JW, Black MA, Bergh J, D'Agostino Jr R et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res 2011; 71: 6728–6737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pinnix ZK, Miller LD, Wang W, D'Agostino Jr R, Kute T, Willingham MC et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010; 2: 43ra56.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Schonberg DL, Miller TE, Wu Q, Flavahan WA, Das NK, Hale JS et al. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell 2015; 28: 441–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tesfay L, Clausen KA, Kim JW, Hegde P, Wang X, Miller LD et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res 2015; 75: 2254–2263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dijkgraaf EM, Welters MJ, Nortier JW, van der Burg SH, Kroep JR . Interleukin-6/interleukin-6 receptor pathway as a new therapy target in epithelial ovarian cancer. Curr Pharm Des 2012; 18: 3816–3827.

    Article  CAS  PubMed  Google Scholar 

  39. Zou M, Zhang X, Xu C . IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in ovarian cancer cells. Cell Oncol (Dordr) 2015.

  40. Lui GY, Kovacevic Z, V Menezes S, Kalinowski DS, Merlot AM, Sahni S et al. Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion. Mol Pharmacol 2015; 87: 543–560.

    Article  PubMed  Google Scholar 

  41. Dai J, Huang C, Wu J, Yang C, Frenkel K, Huang X . Iron-induced interleukin-6 gene expression: possible mediation through the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. Toxicology 2004; 203: 199–209.

    Article  CAS  PubMed  Google Scholar 

  42. Reed JC, Pellecchia M . Ironing out cell death mechanisms. Cell 2012; 149: 963–965.

    Article  CAS  PubMed  Google Scholar 

  43. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang WS, Stockwell BR . Ferroptosis: death by lipid peroxidation. Trends Cell Biol 2015; 26: 165–176.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shah MM, Landen CN . Ovarian cancer stem cells: are they real and why are they important? Gynecol Oncol 2014; 132: 483–489.

    Article  PubMed  Google Scholar 

  46. Deng Z, Wan M, Sui G . PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol cell biol 2007; 27: 3780–3792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ross SL, Tran L, Winters A, Lee KJ, Plewa C, Foltz I et al. Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell metab 2012; 15: 905–917.

    Article  CAS  PubMed  Google Scholar 

  48. Nguyen DH, Zhou T, Shu J, Mao J . Quantifying chromogen intensity in immunohistochemistry via reciprocal intensity. CancerInCytes 2013; 2: 1–3e.

Download references

Acknowledgements

Supported in part by NIH grants R01 CA188025 (SVT), R01 CA171101 (FMT), the Department of Defense (W81XWH-10-1-0289 to CC), and Scholar grants from the Cancer Prevention and Research Institute of Texas (CPRIT; to WX and FM). We thank Tara L Arvedson (Amgen, Thousand Oaks, CA) for a generous gift of anti-ferroportin antibody.

Author information

Author notes

  1. M Lynch

    Present address: 14Current address: Statistical Sciences Group CCS-6, Los Alamos National Laboratory, Los Alamos, NM, USA.,

  2. D Basuli and L Tesfay: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA

    D Basuli, L Tesfay, Z Deng, B Paul & S V Torti

  2. National Cancer Center Research Institute, Tokyo, Japan

    Y Yamamoto

  3. Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    G Ning

  4. Center for Stem Cells and Regenerative Medicine, University of Texas Health Center, Houston, TX, USA

    W Xian

  5. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    F McKeon

  6. Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, CT, USA

    M Lynch

  7. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    C P Crum

  8. Department of Pathology,, University of Connecticut Health Center, Farmington, CT, USA

    P Hegde & X Wang

  9. Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, CT, USA

    M Brewer

  10. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    L D Miller

  11. Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA

    N Dyment

  12. Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA

    F M Torti

Authors
  1. D Basuli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Tesfay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W Xian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F McKeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C P Crum
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Hegde
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Brewer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L D Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. N Dyment
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. F M Torti
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. S V Torti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S V Torti.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Basuli, D., Tesfay, L., Deng, Z. et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36, 4089–4099 (2017). https://doi.org/10.1038/onc.2017.11

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.11

This article is cited by

Search

Advanced search

Quick links