RGD peptides induce apoptosis by direct caspase-3 activation

Citation
Cd. Buckley et al., RGD peptides induce apoptosis by direct caspase-3 activation, NATURE, 397(6719), 1999, pp. 534-539
Citations number
30
Categorie Soggetti
Multidisciplinary,Multidisciplinary,Multidisciplinary
Journal title
NATURE
ISSN journal
00280836 → ACNP
Volume
397
Issue
6719
Year of publication
1999
Pages
534 - 539
Database
ISI
SICI code
0028-0836(19990211)397:6719<534:RPIABD>2.0.ZU;2-G
Abstract
Synthetic peptides containing the arginine-glycine-aspartate (RGD) motif ha ve been used extensively as inhibitors of integrin-ligand interactions in s tudies of cell adhesion, migration, growth and differentiation(1-3), becaus e the RGD motif is an integrin-recognition motif found in many ligands. Her e we report that RGD-containing peptides are able to directly induce apopto sis without any requirement for integrin-mediated cell clustering or signal s. We show that RGD-containing peptides enter cells and directly induce aut oprocessing and enzymatic activity of pro-caspase-3, a pro-apoptotic protei n. Using the breast carcinoma cell line MCF-7, which has a functional delet ion of the caspase-3 gene, we confirm that caspase-3 is required for RGD-me diated cell death, In addition to an RGD motif, pro-caspase-3 also contains a potential RGD-binding motif, aspartate-aspartate-methionine (DDM)(4), ne ar the site of processing to produce the p12 and p17 subunits(5). On the ba sis of the ability of RGD-DDX interactions to trigger integrin activation(6 ), we suggest that RGD peptides induce apoptosis by triggering conformation al changes that promote pro-caspase-3 autoprocessing and activation. These findings provide an alternative molecular explanation for the potent pro-ap optotic properties of RGD peptides in models of angiogenesis, inflammation and cancer metastasis(7-9).