Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with alphavbeta3 and alphavbeta5 integrins.
Canstatin, the noncollagenous domain of collagen type IV alpha-chains, belongs to a series of collagen-derived angiogenic inhibitors. We have elucidated the functional receptors and intracellular signaling induced by canstatin that explain its strong antitumor efficacy in vivo. For this purpose, we generated a canstatin-human serum albumin (CanHSA) fusion protein, employing the HSA moiety as an expression tag. We show that CanHSA triggers a crucial mitochondrial apoptotic mechanism through procaspase-9 cleavage in both endothelial and tumor cells, which is mediated through cross-talk between alphavbeta3- and alphavbeta5-integrin receptors. As a point of reference, we employed the first three kringle domains of angiostatin (K1-3), fused with HSA, which, in contrast to CanHSA, act only on endothelial cells through alphavbeta3-integrin receptor-mediated activation of caspase-8 alone, without ensuing mitochondrial damage. Taken together, these results provide insights into how canstatin might exert its strong anticancer effect.
Magnon
Claire
C
UMR 8121 Laboratoire de vectorologie et transfert de gènes, Institut Gustave Roussy, Villejuif cedex, France. magnon@igr.fr
Galaup
Ariane
A
Mullan
Brian
B
Rouffiac
Valérie
V
Bouquet
Céline
C
Bidart
Jean-Michel
JM
Griscelli
Frank
F
Opolon
Paule
P
Perricaudet
Michel
M
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D007527:Isoenzymes; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D039302:Integrin alphaVbeta3; D016023:Integrins; D007527:Isoenzymes; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C064660:integrin alphaVbeta5; D020169:Caspases