Rhodocetin antagonizes stromal tumor invasion in vitro and other alpha2beta1 integrin-mediated cell functions.
The pleiotropic effects of Calloselasma rhodostoma venom is caused by various toxins, among them kistrin and ancrod, which block platelet activation triggered by RGD-dependent integrins and the blood clotting cascade, respectively. Here, we demonstrate that rhodocetin, another component of this venom, acts as alpha2beta1 integrin inhibiting disintegrin and antagonizes important cellular responses to type I collagen. Cell adhesion, migration, and collagen lattice contraction in vitro were specifically inhibited by rhodocetin, whereas expression of collagen-degrading matrix metalloproteases was differently modulated. Moreover, cell invasion of HT1080 fibrosarcoma cells into a type I collagen matrix, but not into a fibrin gel or a basement membrane-extracted matrigel was efficiently blocked by rhodocetin. Unlike its natural ligand collagen, rhodocetin failed to cluster alpha2beta1 integrin, despite similar binding affinities. Hence, in the absence of focal adhesions cells do not attach firmly to rhodocetin and do not respond with any of alpha2beta1-triggered cell reactions, except for MMP-1 production. Therefore, this disintegrin may be a valuable tool to specifically target stromal tumor invasion and to manipulate other alpha2beta1 integrin-mediated functions, such as excessive scar contraction and fibrosis. Rhodocetin might be therapeutically useful because of its lack of interference with RGD-dependent integrins, low molecular mass, high solubility, and biochemical stability.
Eble
Johannes A
JA
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstrasse 15, 48149, Münster, Germany. eble@uni-muenster.de
Niland
Stephan
S
Dennes
André
A
Schmidt-Hederich
Alletta
A
Bruckner
Peter
P
Brunner
Georg
G
D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D024042:Collagen Type I; D003435:Crotalid Venoms / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000473:pathology*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014407:Tumor Cells, Cultured
D024042:Collagen Type I; D003435:Crotalid Venoms; D038982:Integrin alpha2beta1; C119730:rhodocetin; D020781:Matrix Metalloproteinase 1