title: Cysteine cathepsins S and L modulate anti-angiogenic activities of human endostatin.
abstract: Human endostatin, a potent anti-angiogenic protein, is generated by release of the C terminus of collagen XVIII. Here, we propose that cysteine cathepsins are involved in both the liberation and activation of bioactive endostatin fragments, thus regulating their anti-angiogenic properties. Cathepsins B, S, and L efficiently cleaved in vitro FRET peptides that encompass the hinge region corresponding to the N terminus of endostatin. However, in human umbilical vein endothelial cell-based assays, silencing of cathepsins S and L, but not cathepsin B, impaired the generation of the ∼22-kDa endostatin species. Moreover, cathepsins L and S released two peptides from endostatin with increased angiostatic properties and both encompassing the NGR sequence, a vasculature homing motif. The G10T peptide (residues 1455-1464: collagen XVIII numbering) displayed compelling anti-proliferative (EC(50) = 0.23 nm) and proapoptotic properties. G10T inhibited aminopeptidase N (APN/CD13) and reduced tube formation of endothelial cells in a manner similar to bestatin. Combination of G10T with bestatin resulted in no further increase in anti-angiogenic activity. Taken together, these data suggest that endostatin-derived peptides may represent novel molecular links between cathepsins and APN/CD13 in the regulation of angiogenesis.
authors: INSERM U618, Protéases et Vectorisation Pulmonaires, Université François Rabelais, 37000 Tours, France.
authors: Florian
authors: F
authors: Veillard
authors: Ahlame
authors: A
authors: Saidi
authors: Roberta E
authors: RE
authors: Burden
authors: Christopher J
authors: CJ
authors: Scott
authors: Ludovic
authors: L
authors: Gillet
authors: Fabien
authors: F
authors: Lecaille
authors: Gilles
authors: G
authors: Lalmanach
mesh_terms: D020816:Amino Acid Motifs; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D018826:CD13 Antigens / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D043169:Endostatins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011480:Protease Inhibitors; D002403:Cathepsins; D018826:CD13 Antigens; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; D007930:Leucine; C012211:ubenimex