targeting melanoma metastasis and immunosuppression with a new mode of melanoma inhibitory activity (mia) protein inhibition针对黑色素瘤转移和免疫抑制的新模式(mia)蛋白抑制黑素瘤抑制活动.pdf

Targeting Melanoma Metastasis and Immunosuppression with a New Mode of Melanoma Inhibitory Activity (MIA) Protein Inhibition 1. 2. 3 4 5 6 Jennifer Schmidt , Alexander Riechers , Raphael Stoll , Thomas Amann , Florian Fink , Thilo Spruss , 5 ¨ 2 4 1 Wolfram Gronwald , Burkhard Konig , Claus Hellerbrand , Anja Katrin Bosserhoff * 1 Institute of Pathology, University of Regensburg, Regensburg, Germany, 2 Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany, 3 Faculty of Chemistry and Biochemistry, Biomolecular NMR, Ruhr University of Bochum, Bochum, Germany, 4 Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany, 5 Institute of Functional Genomics, University of Regensburg, Regensburg, Germany, 6 Institute of Pharmacy, University of Regensburg, Regensburg, Germany Abstract Melanoma is the most aggressive form of skin cancer, with fast progression and early dissemination mediated by the melanoma inhibitory activity (MIA) protein. Here, we discovered that dimerization of MIA is required for functional activity through mutagenesis of MIA which showed the correlation between dimerization and functional activity. We subsequently identified the dodecapeptide AR71, which prevents MIA dimerization and thereby acts as a MIA inhibitor. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy demonstrated the binding of AR71 to the MIA dimerization domain, in agreement with in vitro and in vivo data revealing reduced cell migration, reduced formation of metastases and increased immune response after AR71 treatment. We believe AR71 is a lead