The antitumor properties of the alpha3(IV)-(185-203) peptide from the NC1 domain of type IV collagen (tumstatin) are conformation-dependent.
Tumor progression may be controlled by various fragments derived from noncollagenous 1 (NC1) C-terminal domains of type IV collagen. We demonstrated previously that a peptide sequence from the NC1 domain of the alpha3(IV) collagen chain inhibits the in vitro expression of matrix metalloproteinases in human melanoma cells through RGD-independent binding to alpha(v)beta(3) integrin. In the present paper, we demonstrate that in a mouse melanoma model, the NC1 alpha3(IV)-(185-203) peptide inhibits in vivo tumor growth in a conformation-dependent manner. The decrease of tumor growth is the result of an inhibition of cell proliferation and a decrease of cell invasive properties by down-regulation of proteolytic cascades, mainly matrix metalloproteinases and the plasminogen activation system. A shorter peptide comprising the seven N-terminal residues 185-191 (CNYYSNS) shares the same inhibitory profile. The three-dimensional structures of the CNYYSNS and NC1 alpha3(IV)-(185-203) peptides show a beta-turn at the YSNS (188-191) sequence level, which is crucial for biological activity. As well, the homologous MNYYSNS heptapeptide keeps the beta-turn and the inhibitory activity. In contrast, the DNYYSNS heptapeptide, which does not form the beta-turn at the YSNS level, is devoid of inhibitory activity. Structural studies indicate a strong structure-function relationship of the peptides and point to the YSNS turn as necessary for biological activity. These peptides could act as potent and specific antitumor antagonists of alpha(v)beta(3) integrin in melanoma progression.
Laboratory of Spectroscopy and BioMolecular Structures, EA 3305, CNRS Unite Mixte de Recherche 6013, Institut Federatif de Recherche 53 Biomolecules, University of Reims Champagne-Ardenne, Reims F-51095, France.
Nicolas
N
Floquet
Sylvie
S
Pasco
Laurent
L
Ramont
Philippe
P
Derreumaux
Jean Yves
JY
Laronze
Jean Marc
JM
Nuzillard
François Xavier
FX
Maquart
Alain J P
AJ
Alix
Jean Claude
JC
Monboisse
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000737:chemistry* / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D024141:Collagen Type IV / Q000737:chemistry* / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000032:analysis; D005260:Female; D018093:Gelatinases / Q000032:analysis; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D008666:Metalloendopeptidases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001324:Autoantigens; D024141:Collagen Type IV; D004792:Enzyme Precursors; C057112:type IV collagen alpha3 chain; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase