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.