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

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.

Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis

“…For our in vitro assays, we used recombinant human MIF (rMIF), a kind donation from R. Bucala (Yale School of Medicine, Yale University, New Haven, CT, USA). We have previously published our work on the development of an in-house novel small-molecular-weight inhibitor for MIF's enzymatic activity: SCD-19 [3-(29-methylphenyl)-isocoumarin] (12). ISO-1 [(S,R)-3-(4-hydroxyphenyl)4.5-dihydro-5-isoxazole acetic acid methyl ester] is a commercially available inhibitor (VWR, Dublin, Ireland).…”

Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer

“…Blocking of MIF activity either by antibodies or stable RNA interference reduced tumor growth in animal models of colorectal cancer [29], prostate cancer [30], ovarian cancer [20], neuroblastoma [31], pancreatic cancer [10], breast cancer [9], melanoma [22, 32] and lung cancer [28]. The involvement of MIF in human tumor development has been substantiated by reports that describe higher MIF levels in the circulation of cancer patients.…”

Pathophysiology of cancer therapy-provoked atrial fibrillation

“…A previous study also implicated MIF as being involved in electrical remodeling that accompanies AF, probably by decreasing I Ca,L amplitudes through impairment of channel function, down-regulation of LCC α 1C subunit levels, and activation of cSrc kinases in atrial myocytes [121]. Several reports also identified that blocking the function of MIF significantly attenuated cancer growth in vitro or in vivo systems, such as with lung cancer, thyroid cancer, bladder cancer, squamous carcinoma, melanoma, and colon cancer [171][172][173][174][175]. MIF inhibition is deleterious for high-fat diet-induced cardiac dysfunction and antagonizes pressure overload-induced cardiac hypertrophy [176,177].…”