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Molecular Medicine

, Volume 20, Issue 1, pp 729–735 | Cite as

Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer

  • Leona Mawhinney
  • Michelle E. Armstrong
  • Ciaran O’Reilly
  • Richard Bucala
  • Lin Leng
  • Gunter Fingerle-Rowson
  • Darren Fayne
  • Michael P. Keane
  • Aisling Tynan
  • Lewena Maher
  • Gordon Cooke
  • David Lloyd
  • Helen Conroy
  • Seamas C. Donnelly
Research Article

Abstract

The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (MifP1G). Primary tumor growth was significantly attenuated in both Mif-KO and MifP1G mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.

Notes

Acknowledgments

SC Donnelly was supported by grants from Science Foundation Ireland (SFI), the Health Research Board (HRB) and the Irish Lung Foundation (ILF).

R Bucala was supported by National Institutes of Health Grant AI042310. G Fingerle-Rowson was supported by the Jose Carreras Leukaemia Foundation (Grant R06/20) and by the German Research Council (Grant 712/2-2).

Supplementary material

10020_2014_2001729_MOESM1_ESM.pdf (438 kb)
Supplementary material, approximately 438 KB.

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© The Author(s) 2014

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Authors and Affiliations

  • Leona Mawhinney
    • 1
    • 6
  • Michelle E. Armstrong
    • 1
  • Ciaran O’Reilly
    • 2
  • Richard Bucala
    • 3
  • Lin Leng
    • 3
  • Gunter Fingerle-Rowson
    • 4
  • Darren Fayne
    • 2
  • Michael P. Keane
    • 1
  • Aisling Tynan
    • 1
  • Lewena Maher
    • 1
  • Gordon Cooke
    • 1
  • David Lloyd
    • 5
  • Helen Conroy
    • 1
  • Seamas C. Donnelly
    • 1
  1. 1.Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical ScienceUniversity College DublinDublinIreland
  2. 2.Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences InstituteTrinity College DublinDublinIreland
  3. 3.Department of Internal MedicineYale University School of MedicineNew HavenUSA
  4. 4.Department of Internal Medicine 1University Hospital Cologne, Centre for Integrated Oncology Köln-BonnCologneGermany
  5. 5.Division of Health SciencesUniversity of South AustraliaAdelaideAustralia
  6. 6.School of MedicineTrinity Biomedical Science Institute, Trinity College DublinDublin 2Ireland

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