Targeting melanoma metastasis and immunosuppression with a new mode of melanoma inhibitory activity (MIA) protein inhibition.
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 structure for MIA inhibitors. More generally, inhibiting MIA dimerization is a novel therapeutic concept in melanoma therapy.
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Jennifer
J
Schmidt
Alexander
A
Riechers
Raphael
R
Stoll
Thomas
T
Amann
Florian
F
Fink
Thilo
T
Spruss
Wolfram
W
Gronwald
Burkhard
B
König
Claus
C
Hellerbrand
Anja Katrin
AK
Bosserhoff
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy / Q000379:methods*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary
D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D009842:Oligopeptides; C000595066:acetyl-phenylalanyl-histidyl-tryptophyl-arginyl-tyrosyl-prolyl-leucyl-prolyl-leucyl-prolyl-glycyl-glutaminamide