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Canstatin Acts on Endothelial and Tumor Cells via Mitochondrial Damage Initiated through Interaction with _vß₃ and _vß₅ Integrins

¹ UMR 8121 Laboratoire de vectorologie et transfert de gènes, ² Laboratoire d'imagerie du petit animal, and ³ Département de biologie clinique, Institut Gustave Roussy, Villejuif cedex, France

Requests for reprints: Claire Magnon, UMR 8121, PR2, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif cedex, France. Phone: 33-1-42115075; Fax: 33-1-42115245; E-mail: magnon{at}igr.fr.

Canstatin, the noncollagenous domain of collagen type IV -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 _vß₃- and _vß₅-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 _vß₃-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.

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