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.

  • Article
  • Published:

Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment

Oncogene volume 40, pages 6248–6257 (2021)Cite this article

Subjects

A Correction to this article was published on 15 March 2023

This article has been updated

Abstract

The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (ES-2 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and ES-2 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian cancer and potentially other DIO3-dependent malignancies.

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

Fig. 1: Kaplan–Meier analysis for DIO3 and disease markers with overall survival in HGSOC patients.
Fig. 2: Design and efficacy of novel DIO3 inhibitors in HGSOC cells.
Fig. 3: Induction of apoptosis and attenuation of cell proliferation and T3-related proteins in HGSOC cells treated with the DIO3 inhibitors.
Fig. 4: DIO3 inhibitors suppress tumor growth in HGSOC xenograft model.
Fig. 5: DIO3-silenced tumors are unaffected by the drugs.
Fig. 6: Illustration of DIO3 enzymatic activity and inhibition in cancer cells.

Similar content being viewed by others

Change history

References

  1. Luongo C, Dentice M, Salvatore D. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol. 2019;15:479–88.

    Article  PubMed  Google Scholar 

  2. Goemann IM, Marczyk VR, Romitti M, Wajner SM, Maia AL. Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias. Endocr Relat Cancer. 2018;25:R625–R645.

    Article  CAS  PubMed  Google Scholar 

  3. Goemann IM, Romitti M, Meyer ELS, Wajner SM, Maia AL. Role of thyroid hormones in the neoplastic process: an overview. Endocr Relat Cancer. 2017;24:R367–R385.

    Article  CAS  PubMed  Google Scholar 

  4. Catalano V, Dentice M, Ambrosio R, Luongo C, Carollo R, Benfante A, et al. Activated thyroid hormone promotes differentiation and chemotherapeutic sensitization of colorectal cancer stem cells by regulating Wnt and BMP4 signaling. Cancer Res. 2016;76:1237–44.

    Article  CAS  PubMed  Google Scholar 

  5. Dentice M, Luongo C, Ambrosio R, Sibilio A, Casillo A, Iaccarino A, et al. beta-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. Gastroenterology. 2012;143:1037–47.

    Article  CAS  PubMed  Google Scholar 

  6. Dentice M, Luongo C, Huang S, Ambrosio R, Elefante A, Mirebeau-Prunier D, et al. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci USA. 2007;104:14466–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Di Girolamo D, Ambrosio R, De Stefano MA, Mancino G, Porcelli T, Luongo C, et al. Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway–driven skin tumorigenesis. J Clin Investig. 2016;126:2308–20.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Romitti M, Wajner SM, Ceolin L, Ferreira CV, Ribeiro R, Rohenkohl HC, et al. MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocr Relat Cancer. 2016;23:135–46.

    Article  CAS  PubMed  Google Scholar 

  9. Nappi A, De Stefano MA, Dentice M, Salvatore D. Deiodinases and cancer. Endocrinology. 2021;162:bqab016.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Moskovich D, Alfandari A, Finkelshtein Y, Weisz A, Katzav A, Kidron D, et al. DIO3, the thyroid hormone inactivating enzyme, promotes tumorigenesis and metabolic reprogramming in high grade serous ovarian cancer. Cancer Lett. 2021;501:224–33.

    Article  CAS  PubMed  Google Scholar 

  11. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  PubMed  Google Scholar 

  12. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    Article  PubMed  Google Scholar 

  13. Renko K, Schäche S, Hoefig CS, Welsink T, Schwiebert C, Braun D, et al. An improved nonradioactive screening method identifies genistein and xanthohumol as potent inhibitors of iodothyronine deiodinases. Thyroid. 2015;25:962–8.

  14. Steegborn C, Schweizer U. Structure and mechanism of iodothyronine deiodinases–what we know, what we don’t know, and what would be nice to know. Exp Clin Endocrinol Diabetes. 2020;128:375–8.

  15. Manna D, Mugesh G. A chemical model for the inner‐ring deiodination of thyroxine by iodothyronine deiodinase. Angew Chem Int Ed. 2010;49:9246–9.

    Article  CAS  Google Scholar 

  16. Manna D, Mugesh G. Deiodination of thyroid hormones by iodothyronine deiodinase mimics: does an increase in the reactivity alter the regioselectivity? J Am Chem Soc. 2011;133:9980–3.

    Article  CAS  PubMed  Google Scholar 

  17. Manna D, Mugesh G. Regioselective deiodination of thyroxine by iodothyronine deiodinase mimics: an unusual mechanistic pathway involving cooperative chalcogen and halogen bonding. J Am Chem Soc. 2012;134:4269–79.

    Article  CAS  PubMed  Google Scholar 

  18. Mondal S, Mugesh G. Biomimetic deiodination of thyroid hormones and iodothyronamines–a structure–activity relationship study. Org Biomolecular Chem. 2016;14:9490–9500.

    Article  CAS  Google Scholar 

  19. Raja K, Mugesh G. Remarkable effect of chalcogen substitution on an enzyme mimetic for deiodination of thyroid hormones. Angew Chem Int Ed. 2015;54:7674–8.

    Article  CAS  Google Scholar 

  20. Győrffy B, Lánczky A, Szállási Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19:197–208.

    Article  PubMed  Google Scholar 

  21. Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C. Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism. Proc Natl Acad Sci USA. 2014;111:10526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Yaginuma Y, Westphal H. Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. Cancer Res. 1992;52:4196–9.

    CAS  PubMed  Google Scholar 

  24. Bargonetti J, Prives C. Gain-of-function mutant p53: history and speculation. J Mol Cell Biol. 2019;11:605–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cole AJ, Dwight T, Gill AJ, Dickson K-A, Zhu Y, Clarkson A, et al. Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing. Sci Rep. 2016;6:1–12.

    Article  Google Scholar 

  26. Simpkins F, Jang K, Yoon H, Hew KE, Kim M, Azzam DJ, et al. Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells. Clin Cancer Res. 2018;24:4874–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nguyen VHL, Hough R, Bernaudo S, Peng C. Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis. J Ovarian Res. 2019;12:1–17.

    Article  Google Scholar 

  28. Ghannam-Shahbari D, Jacob E, Kakun RR, Wasserman T, Korsensky L, Sternfeld O, et al. PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma. Oncogene. 2018;37:2213–24.

  29. Dentice M, Antonini D, Salvatore D. Type 3 deiodinase and solid tumors: an intriguing pair. Expert Opin Ther Targets. 2013;17:1369–79.

    Article  CAS  PubMed  Google Scholar 

  30. Hernandes MZ, Cavalcanti SMT, Moreira DRM, de Azevedo Junior WF, Leite ACL. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr Drug Targets. 2010;11:303–14.

    Article  CAS  PubMed  Google Scholar 

  31. Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem. 2013;56:1363–88.

    Article  CAS  PubMed  Google Scholar 

  32. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N. Engl J Med. 2019;381:1632–43.

    Article  CAS  PubMed  Google Scholar 

  33. Dhillon S. Lonafarnib: first approval. Drugs. 2021;81:283–9.

  34. Smith BD, Kaufman MD, Lu W-P, Gupta A, Leary CB, Wise SC, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35:738–51.e739.

    Article  CAS  PubMed  Google Scholar 

  35. Andrea VR. The role of halogen bonding in inhibitor recognition and binding by protein kinases. Curr Top Med Chem. 2007;7:1336–48.

    Article  Google Scholar 

  36. Wasik R, Łebska M, Felczak K, Poznański J, Shugar D. Relative role of halogen bonds and hydrophobic interactions in inhibition of human protein kinase CK2α by tetrabromobenzotriazole and some C (5)-substituted analogues. J Phys Chem B. 2010;114:10601–11.

    Article  CAS  PubMed  Google Scholar 

  37. Contreras-Jurado C, Alonso-Merino E, Saiz-Ladera C, Valiño AJ, Regadera J, Alemany S, et al. The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia. Sci Rep. 2016;6:1–12.

    Article  Google Scholar 

  38. Suarez J, Scott BT, Suarez-Ramirez JA, Chavira CV, Dillmann WH. Thyroid hormone inhibits ERK phosphorylation in pressure overload-induced hypertrophied mouse hearts through a receptor-mediated mechanism. Am J Physiol Cell Physiol. 2010;299:C1524–C1529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Flores-Morales A, Gullberg H, Fernandez L, Ståhlberg N, Lee NH, Vennström B, et al. Patterns of liver gene expression governed by TRβ. Mol Endocrinol. 2002;16:1257–68.

    CAS  PubMed  Google Scholar 

  40. García-Silva S, Aranda A. The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol Cell Biol. 2004;24:7514–23.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Punchihewa C, Inoue A, Hishiki A, Fujikawa Y, Connelly M, Evison B, et al. Identification of small molecule proliferating cell nuclear antigen (PCNA) inhibitor that disrupts interactions with PIP-box proteins and inhibits DNA replication. J Biol Chem. 2012;287:14289–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Perez-Juste G, Aranda A. The cyclin-dependent kinase inhibitor p27Kip1 is involved in thyroid hormone-mediated neuronal differentiation. J Biol Chem. 1999;274:5026–31.

    Article  CAS  PubMed  Google Scholar 

  43. Pérez-Juste G, Garcı́a-Silva S, Aranda A. An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells. J Biol Chem. 2000;275:1307–14.

    Article  PubMed  Google Scholar 

  44. Gagne R, Green JR, Dong H, Wade MG, Yauk CL. Identification of thyroid hormone receptor binding sites in developing mouse cerebellum. BMC Genomics. 2013;14:1–14.

    Article  Google Scholar 

  45. Nappi A, Murolo M, Sagliocchi S, Miro C, Cicatiello AG, Di Cicco E, et al. Selective inhibition of genomic and non-genomic effects of thyroid hormone regulates muscle cell differentiation and metabolic behavior. Int J Mol Sci. 2021;22:7175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Porlan E, Vidaurre OG, Rodríguez-Peña A. Thyroid hormone receptor-β (TRβ1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2. Oncogene. 2008;27:2795–800.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shinderman-Maman E, Cohen K, Weingarten C, Nabriski D, Twito O, Baraf L, et al. The thyroid hormone-alphavbeta3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene. 2016;35:1977–87.

    Article  CAS  PubMed  Google Scholar 

  49. Cohen K, Ellis M, Khoury S, Davis PJ, Hercbergs A, Ashur-Fabian O. Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via alphavbeta3 integrin. Mol Cancer Res. 2011;9:1385–94.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of DM was done in partial fulfillment of the requirements for a PhD degree from the Sackler Faculty of Medicine, Tel Aviv University, Israel. OA-F and BL received support from the Israel Innovation Authority, Nofar Program for Applied Research in Academia, Ministry of Economics (Project 59435).

Author information

Authors and Affiliations

  1. Translational Oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel

    Dotan Moskovich, Yael Finkelshtein, Adi Alfandari, Amit Rosemarin, Martin Ellis & Osnat Ashur-Fabian

  2. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Dotan Moskovich, Yael Finkelshtein, Adi Alfandari, Amit Rosemarin & Osnat Ashur-Fabian

  3. Biological Psychiatry Laboratory Hadassah – Hebrew University Medical Center, Jerusalem, Israel

    Tzuri Lifschytz & Bernard Lerer

  4. Department of Pathology, Meir Medical Center, Kfar Saba, Israel

    Avivit Weisz, Aviva Katzav & Debora Kidron

  5. Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India

    Santanu Mondal, Harinarayana Ungati & Govindasamy Mugesh

  6. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Debora Kidron & Martin Ellis

Authors
  1. Dotan Moskovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yael Finkelshtein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adi Alfandari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amit Rosemarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tzuri Lifschytz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avivit Weisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Santanu Mondal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Harinarayana Ungati
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aviva Katzav
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Debora Kidron
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Govindasamy Mugesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bernard Lerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Osnat Ashur-Fabian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DM preformed, analyzed, and interpreted the experimental data. AA, AR, and YF performed some of the methods. AW, AK, and DK assisted in the IHC assays. GM, TL, and BL designed and developed the DIO3 inhibitors. SM and HU performed enzymatic inhibition assays. OA-F designed, analyzed, and interpreted the experimental data. DM, GM, BL, ME, and OA-F wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Osnat Ashur-Fabian.

Ethics declarations

Competing interests

BL, GM, TL, and OA-F hold a patent for DIO3 inhibitors or are involved in patent commercialization. The other authors declare no potential conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moskovich, D., Finkelshtein, Y., Alfandari, A. et al. Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment. Oncogene 40, 6248–6257 (2021). https://doi.org/10.1038/s41388-021-02020-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-02020-z

This article is cited by

Search

Advanced search

Quick links