Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with alphavbeta3 and alphavbeta5 integrins

Cancer Res. 2005 May 15;65(10):4353-61. doi: 10.1158/0008-5472.CAN-04-3536.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / metabolism
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • Collagen Type IV / pharmacology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Humans
  • Integrin alphaVbeta3 / metabolism*
  • Integrins / metabolism*
  • Isoenzymes
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Protein Structure, Tertiary
  • Receptors, Vitronectin / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Serum Albumin / genetics
  • Serum Albumin / metabolism
  • Serum Albumin / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Collagen Type IV
  • Integrin alphaVbeta3
  • Integrins
  • Isoenzymes
  • Receptors, Vitronectin
  • Recombinant Fusion Proteins
  • Serum Albumin
  • integrin alphaVbeta5
  • Caspases