Universität zu Köln

Mawhinney, Leona, Armstrong, Michelle E. ORCID: 0000-0001-7729-755X, O'Reilly, Ciaran ORCID: 0000-0001-8926-1853, Bucala, Richard, Leng, Lin ORCID: 0000-0002-0605-358X, Fingerle-Rowson, Gunter, Fayne, Darren ORCID: 0000-0003-2417-5406, Keane, Michael P., Tynan, Aisling ORCID: 0000-0002-6856-2259, Maher, Lewena, Cooke, Gordon ORCID: 0000-0003-0366-3603, Lloyd, David ORCID: 0000-0003-0658-8995, Conroy, Helen ORCID: 0000-0002-5857-2760 and Donnelly, Seamas C. (2014). Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer. Mol. Med., 20. S. 729 - 736. MANHASSET: FEINSTEIN INST MED RES. ISSN 1528-3658

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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 (Mif(P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif(P1G) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mawhinney, Leona UNSPECIFIED UNSPECIFIED UNSPECIFIED Armstrong, Michelle E. UNSPECIFIED orcid.org/0000-0001-7729-755X UNSPECIFIED O'Reilly, Ciaran UNSPECIFIED orcid.org/0000-0001-8926-1853 UNSPECIFIED Bucala, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Leng, Lin UNSPECIFIED orcid.org/0000-0002-0605-358X UNSPECIFIED Fingerle-Rowson, Gunter UNSPECIFIED UNSPECIFIED UNSPECIFIED Fayne, Darren UNSPECIFIED orcid.org/0000-0003-2417-5406 UNSPECIFIED Keane, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tynan, Aisling UNSPECIFIED orcid.org/0000-0002-6856-2259 UNSPECIFIED Maher, Lewena UNSPECIFIED UNSPECIFIED UNSPECIFIED Cooke, Gordon UNSPECIFIED orcid.org/0000-0003-0366-3603 UNSPECIFIED Lloyd, David UNSPECIFIED orcid.org/0000-0003-0658-8995 UNSPECIFIED Conroy, Helen UNSPECIFIED orcid.org/0000-0002-5857-2760 UNSPECIFIED Donnelly, Seamas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-435383
DOI:	10.2119/molmed.2014.00136
Journal or Publication Title:	Mol. Med.
Volume:	20
Page Range:	S. 729 - 736
Date:	2014
Publisher:	FEINSTEIN INST MED RES
Place of Publication:	MANHASSET
ISSN:	1528-3658
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROMOTES TUMOR-GROWTH; REGULATORY ROLE; CYSTIC-FIBROSIS; CELL-MIGRATION; EXPRESSION; INFLAMMATION; ACTIVATION; INVASION; RECEPTOR; CD74 Multiple languages Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43538